TMC1 p.Ala615=
c.1845C>T · rs746329878 · VCV2962711
Likely benign
Single submitter
Classification
Likely benign
ClinVar
Review
Single submitter ★☆☆☆
ClinVar · 1 submitter
gnomAD v4.1
Rare
ultra-rare (popmax 0.0165%, mid)
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| Splicing | ||
| SpliceAI | <0.2 | no splice effect predicted · four deltas, not one · how we know |
|---|---|---|
| Constraint at this position | ||
| Conservation | phyloP -6 | GERP -4.1 |
| Overall | ||
| CADD | 5.872 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.0165%
Middle Eastern · 1/6,062 alleles
Filtering AF
0.00103%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.00083%
Overall
0.00161%
26/1,614,116 alleles · ultra-rare
exomes 24/1,461,890 · genomes 2/152,226 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| Middle Easterngrpmax | 0.0165% | 6,062 |
| South Asian | 0.00329% | 30,355 |
| Admixed American | 0.00167% | 60,014 |
| European (non-Finnish) | 0.00161% | 62,106 |
| Remaining individualsnot grpmax-eligible | 0.0016% | 62,510 |
| African / African-American | 0.00133% | 75,018 |
Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.
Variant & gene context
- Gene
- TMC1
- Protein
- p.Ala615=
- Coding
- c.1845C>T
- MANE Select
- NM_138691
- dbSNP
- rs746329878
- Type
- single nucleotide variant
- Location
- chr9:72820923 (GRCh38)
- Gene constraint
- LOEUF 0.914 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 76.96 · 1 PDB
Similar variants
- TMC1 c.1405-2A>T Likely pathogenic ★★ same type
- TMC1 c.1763+3A>G Pathogenic/Likely pathogenic ★★ same type
- TMC1 c.236+1G>A Pathogenic ★★ same type
- TMC1 c.236+1G>T Pathogenic ★★ same type
- TMC1 c.64+2T>A Pathogenic/Likely pathogenic ★★ same type
- TMC1 c.741+1G>A Pathogenic/Likely pathogenic ★★ same type
- TMC1 c.884+1G>A Pathogenic ★★ same type
- TMC1 p.Arg264Ter Pathogenic ★★ same type
Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →
Cite Sugi Variant
Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/tmc1-p-ala615 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown