Is TMC1 p.Ala726Val (c.2177C>T) pathogenic?

TMC1 p.Ala726Val (c.2177C>T) is classified Uncertain significance in TMC1 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-07-10). AlphaMissense: likely benign (0.2276); Very rare (popmax 0.00958%, nfe); Associated with autosomal dominant nonsyndromic hearing loss 36.

What condition is associated with TMC1 p.Ala726Val (c.2177C>T)?

TMC1 p.Ala726Val (c.2177C>T) is associated with autosomal dominant nonsyndromic hearing loss 36, autosomal recessive nonsyndromic hearing loss 7 (ClinVar).

How common is TMC1 p.Ala726Val (c.2177C>T) in the general population?

TMC1 p.Ala726Val (c.2177C>T) is very rare (popmax 0.00958%, nfe) (gnomAD).

What do computational predictors say about TMC1 p.Ala726Val (c.2177C>T)?

AlphaMissense predicts likely benign (score 0.2276) — an in-silico prediction, not a clinical call.

TMC1 p.Ala726Val

c.2177C>T · rs573874378 · VCV594638

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.2276 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00958%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autosomal dominant nonsyndromic hearing loss 36

Computational evidence

Protein change
AlphaMissense	0.2276	likely benign
REVEL	0.147	moderately benign-leaning
SaProt	LLR -6.21	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.1	GERP 2, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 187 kb · p 0.0013 · regional, not allelic
Overall
CADD	24.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00958% European (non-Finnish) · 113/1,179,632 alleles

Filtering AF 0.00809% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0076%

Overall 0.00769% 124/1,613,204 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00958%	10,439
Remaining individualsnot grpmax-eligible	0.00801%	12,492
East Asian	0.00446%	22,434
Finnishnot grpmax-eligible	0.00313%	31,965
Admixed American	0.00167%	59,938
African / African-American	0.00134%	74,804

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.Ala726Val
Coding: c.2177C>T
MANE Select: NM_138691
dbSNP: rs573874378
Type: single nucleotide variant
Location: chr9:72830498 (GRCh38)
Gene constraint: LOEUF 0.914 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.96 · 1 PDB

Full TMC1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

autosomal dominant nonsyndromic hearing loss 36 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: autosomal recessive nonsyndromic hearing loss 7

Similar variants

TMC1 p.Ala726fs Likely pathogenic ★ same residue
TMC1 p.Ala726= Likely benign ★★ same residue
TMC1 c.1405-2A>T Likely pathogenic ★★ same condition
TMC1 c.1763+3A>G Pathogenic/Likely pathogenic ★★ same condition
TMC1 c.236+1G>A Pathogenic ★★ same condition
TMC1 c.64+2T>A Pathogenic/Likely pathogenic ★★ same condition
TMC1 c.741+1G>A Pathogenic/Likely pathogenic ★★ same condition
TMC1 c.884+1G>A Pathogenic ★★ same condition

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-ala726val (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown