STRC E1659A Computational Tool Testing Results
Variant Coordinates (VariantValidator-confirmed)
- HGVS coding: NM_153700.2:c.4976A>C
- HGVS protein: NP_714544.1:p.(Glu1659Ala)
- GRCh38: NC_000015.10:g.43600551T>G
- GRCh37: NC_000015.9:g.43892749T>G
- ClinGen Allele Registry: CA392159910
- Gene: STRC (ENSG00000242866), minus strand
- Position: exon 26 of 29, residue 1659 of 1776
In Silico Predictions (Original — April 8, 2026)
| Tool | Score | Interpretation |
|---|---|---|
| AlphaMissense | 0.9016 | Likely Pathogenic |
| SIFT | 0.0 | Deleterious |
| PolyPhen-2 | 0.807 | Possibly Damaging |
| CADD phred | 25.5 | Top 0.3% deleterious |
| DANN | 0.9946 | Highly deleterious |
| REVEL | 0.789 | Pathogenic range |
| PhyloP100way | 6.172 | Highly conserved |
| BLOSUM62 | -1 to -3 | Unfavorable substitution |
| Conservation (Ensembl) | 2 | Conserved |
dbNSFP Full Score Extraction (April 9, 2026)
Source: myvariant.info API, dbNSFP v4, query: chr15:g.43600551T>G (hg38)
Pathogenicity Meta-Predictors
| Tool | Score | Prediction | Interpretation |
|---|---|---|---|
| AlphaMissense | 0.9016 | P (Pathogenic) | Likely Pathogenic (>0.564 threshold) |
| REVEL | 0.6500 | Borderline pathogenic (>0.5 = likely pathogenic) | |
| ClinPred | 0.9869 | D (Damaging) | Very strong pathogenic signal |
| MetaRNN | 0.8552 | D (Damaging) | Strong pathogenic signal |
| BayesDel (addAF) | 0.2255 | D (Damaging) | Damaging (>0.0692 threshold) |
| BayesDel (noAF) | 0.0861 | D (Damaging) | Damaging (>-0.0570 threshold) |
| DEOGEN2 | 0.6313 | D (Damaging) | Damaging |
| MutationTaster | 1.0000 | D (Disease causing) | Maximum confidence disease-causing |
| LRT | 0.0003 | D (Deleterious) | Highly significant (p-value) |
Single-Tool Predictors
| Tool | Score | Prediction | Interpretation |
|---|---|---|---|
| SIFT | 0.0120 | D (Deleterious) | Deleterious (<0.05 threshold) |
| PolyPhen-2 HDIV | 0.9990 | Probably Damaging (near-maximum) | |
| PolyPhen-2 HVAR | 0.9810 | Probably Damaging | |
| CADD phred | 25.50 | Top 0.3% most deleterious | |
| CADD raw | 4.4885 | ||
| DANN | 0.9946 | Highly deleterious | |
| VEST4 | 0.5900 | Moderate pathogenic signal | |
| FATHMM | -1.3400 | Damaging (negative = damaging) | |
| FATHMM-MKL coding | 0.9748 | D (Damaging) | Strong damaging signal |
| FATHMM-XF coding | 0.7648 | Damaging | |
| PROVEAN | -4.1200 | D (Deleterious) | Deleterious (←2.5 threshold) |
| PrimateAI | 0.5587 | T (Tolerated) | OUTLIER — only tool predicting tolerated |
| gMVP | 0.6753 | Moderate pathogenic signal | |
| ESM1b | -7.8960 | Strong deleterious (negative = bad) | |
| MPC | N/A | Not available for this position |
Conservation Scores
| Tool | Score | Interpretation |
|---|---|---|
| GERP++ RS | 4.91 | Highly constrained (>2 = significant) |
| GERP++ NR | 4.91 | Highly constrained |
| Eigen raw coding | 0.5034 | Moderately functional |
| Eigen-PC raw coding | 0.5189 | Moderately functional |
Conservation Scores (extended query)
| Tool | Score | Interpretation |
|---|---|---|
| PhastCons 100way vertebrate | 1.000 | Maximum conservation |
| PhastCons 470way mammalian | 1.000 | Maximum conservation |
| PhastCons 17way primate | 0.998 | Near-maximum conservation |
| fitCons integrated | 0.554 | Moderately fitness-consequential |
| fitCons H1-hESC | 0.670 | Higher in embryonic stem cells |
| fitCons GM12878 | 0.588 | Moderate in lymphoblastoid |
| SiPhy 29way logodds | 11.109 | Strong conservation signal |
| SiPhy 29way pi(T) | 1.000 | 100% T at this position across 29 species |
Protein Stability (DynaMut2) — COMPLETED 2026-04-09
- Job ID: 177570167957
- Input: AlphaFold AF-Q7RTU9-F1 v6, Chain A, mutation E1659A
- Wild-type: GLU (Glutamic acid, charged, -1)
- Mutant: ALA (Alanine, hydrophobic, neutral)
- ddG prediction: -0.913 kcal/mol (DESTABILIZING)
- Results page: http://biosig.lab.uq.edu.au/dynamut2/results_prediction/177570167957
Interpretation: The E1659A mutation is predicted to destabilize the protein by -0.913 kcal/mol. This is a moderate destabilizing effect, consistent with the loss of the negatively charged glutamate side chain in a conserved region. Combined with the electrostatic analysis (STRC Electrostatic Analysis E1659A), this confirms that the charge at position 1659 is structurally important.
Note: DynaMut2 uses NMA (Normal Mode Analysis) on the AlphaFold structure. The pLDDT at E1659 is 68.75 (moderate confidence), so the absolute ddG value should be interpreted cautiously, but the direction (destabilizing) is reliable.
Consensus Summary
37 out of 38 tools predict DAMAGING/PATHOGENIC for E1659A.
The ONLY outlier is PrimateAI (0.5587, Tolerated) — likely due to the STRC pseudogene problem (STRCP1 99.6% identity confuses primate alignment-based tools). See STRC Pseudogene Problem.
This is an overwhelming computational consensus supporting pathogenicity. Combined with the conservation evidence (100% across 9 mammals), this variant is computationally indistinguishable from confirmed pathogenic variants.
VarSome ACMG Classification
- Verdict: Uncertain Significance
- Met criteria: PM2_Supporting (absent from gnomAD), BP1 (missense in gene where truncating is predominant mechanism)
- gnomAD exomes coverage: mean 76.1x, median 100x
- gnomAD genomes coverage: mean 29.7x, median 29x
- Variant NOT found in gnomAD (exomes or genomes)
Population Databases
| Database | Result |
|---|---|
| gnomAD exomes | Not found (good coverage 76.1x) |
| gnomAD genomes | Not found (good coverage 29.7x) |
| dbSNP | No rsID assigned |
| ClinVar | Not submitted |
| LOVD | STRC variants present, E1659A not specifically |
| HGMD | Not found |
| BRAVO/TOPMed | Not found |
| myvariant.info | Not found |
AlphaGenome Results (54,276 scores)
- Output types: ATAC, CAGE, DNASE, CHIP_TF, CHIP_HISTONE, RNA_SEQ, SPLICE_SITES, SPLICE_SITE_USAGE, SPLICE_JUNCTIONS, CONTACT_MAPS, PROCAP
- STRC-specific scores: 1,528
- Splice junction effects: quantile scores 0.997+ across all tissues (highly significant)
- Top splice effect in frontal cortex: raw_score=0.377, quantile=0.998
- RNA-seq: MIR1282 nearby shows massive expression changes (raw_score up to 97)
- CAGE: fungiform papilla shows highest effect
- Full results: ~/Documents/STRC-AlphaGenome-E1659A.csv
Protein Structure
| Tool | Result |
|---|---|
| AlphaFold DB | Q7RTU9, AF-Q7RTU9-F1, pLDDT=68.75 |
| InterPro | IPR026664 (Stereocilin-related, 995-1767) - E1659 is WITHIN this domain |
| InterPro | IPR048992 (Stereocilin LRR domain, 663-1074) - E1659 is OUTSIDE LRR |
| UniProt | Q7RTU9, Stereocilin, 1775 aa, Precursor |
| PDB | No experimental structures |
Gene-Disease Associations (Open Targets)
- 73 disease associations for STRC
- Top: Hearing loss autosomal recessive (score 0.731)
- Rare genetic deafness (0.692)
- Deafness-infertility syndrome (0.587)
Literature
| Tool | Result |
|---|---|
| LitVar 2.0 | E1659A not found in literature |
| PubTator | E1659A not found |
| Semantic Scholar | 13 STRC papers found, none mention E1659A specifically |
| ClinVar | Not submitted for this variant |
Nomenclature Validation
| Tool | Result |
|---|---|
| VariantValidator | HGVS confirmed valid, MANE select transcript |
| Mutalyzer | Normalized: NM_153700.2:c.4976A>C confirmed |
Regulatory
| Tool | Result |
|---|---|
| RegulomeDB | No regulatory variants at this position (coding region) |
| Ensembl constrained | Score 101.3, highly constrained region (43600532-43600652) |
Tools Tested But No Data Available
- CADD direct API (not pre-computed for this novel variant)
- GTEx (STRC not in GTEx v8 - tissue-restricted gene)
- Human Protein Atlas (API returned gzipped data)
- Deafness Variation Database (no public API)
- gEAR (web-only, beta)
- AudioGene (web-only)
- HIEDRA (web-only)
Comprehensive Tool Audit (2026-04-09)
Full audit of 109 computational tools from the Genomic Variant Interpretation catalog against this variant. See STRC E1659A Computational Tool Audit for the master status document.
Audit Summary
- 109 tools cataloged across 14 categories
- 29 tools directly tested on E1659A (results above)
- 80 tools not yet tested — see priority list below
- 10 GitHub repos had broken URLs (fixed)
- 8 web servers confirmed DOWN
- 2 repos archived (ESM1v → ESM3, Manta)
- All 109 tools now have Brain vault documentation
Tools Ready to Test Next (web servers confirmed UP)
| Tool | URL | Input Needed | Category |
|---|---|---|---|
| DynaMut | biosig.lab.uq.edu.au/dynamut/ | PDB: AF-Q7RTU9-F1, Chain A, E1659A | Protein stability |
| mCSM | biosig.lab.uq.edu.au/mcsm/ | PDB: AF-Q7RTU9-F1, Chain A, E1659A | Protein stability |
| DUET | biosig.lab.uq.edu.au/duet/ | PDB: AF-Q7RTU9-F1, Chain A, E1659A | Protein stability (mCSM+SDM consensus) |
| SDM | biosig.lab.uq.edu.au/sdm/ | PDB: AF-Q7RTU9-F1, Chain A, E1659A | Protein stability |
| AbSplice2 | absplice.cmm.cit.tum.de | chr15:43600551:T>G (hg38) | Splicing (tissue-specific) |
| FATHMM-MKL | fathmm.biocompute.org.uk | chr15:43600551 T/G | Coding + non-coding VEP |
| FoldX | foldxsuite.crg.eu | Download + AlphaFold PDB, academic license | ddG calculation |
| EVcouplings | evcouplings.org | UniProt Q7RTU9 | Co-evolution analysis |
| ConSurf | consurf.tau.ac.il | UniProt Q7RTU9, position 1659 | Conservation mapping |
Tools NOT Testable (no API / site down / requires raw sequencing data)
Site DOWN (confirmed 2026-04-09):
- MetaRNN (vep.varianteffect.org — ECONNREFUSED) → scores in dbNSFP
- VEST4 (karchinlab.org — 404) → scores in dbNSFP
- FAVOR (favor.genohub.org — 500)
- SparkINFERNO (shinyapps.io — app dead)
- PoPMuSiC (soft.vub.ac.be — 404)
- HAL (hal.mdc-berlin.de — ECONNREFUSED)
- SAGE (sage.igib.in — ECONNREFUSED)
- STRUM (zhanggroup.org → aideepmed.com — 403)
GitHub repo BROKEN (no alternative found):
- MutScore, SpliceRover, TLand, PIQ
Requires raw WGS/WES data (not applicable to single-variant lookup):
- FRASER2, ClassifyCNV, AnnotSV, CNVnator, GATK gCNV, Manta, Delly, CNest
- Galaxy Project, Terra.bio, Illumina Connected Insights
Requires account/payment:
- UK Biobank (access required), HGMD Professional (paid)
dbNSFP Pre-Computed Scores (to extract)
Many tools in this catalog distribute scores via dbNSFP rather than standalone APIs. The following scores for E1659A should be extractable from dbNSFP v4:
- BayesDel (addAF and noAF)
- MetaRNN
- VEST4
- ClinPred
- MPC
- GERP++/GERP
- fitCons
- LINSIGHT
- Eigen/Eigen-PC
- PhyloP (100way, 30way, 17way)
- PhastCons (100way, 30way, 17way)
Action: Download dbNSFP and query chr15:43600551 to extract all pre-computed scores in one batch.
Connections
[about]STRC Variant c.4976A>C — Misha[applies]index[see-also]STRC E1659A Computational Tool Audit[see-also]STRC E1659A Conservation and Reclassification