Is TMC1 p.Ser208Arg (c.624C>A) pathogenic?

TMC1 p.Ser208Arg (c.624C>A) is classified Uncertain significance in TMC1 (ClinVar, Single submitter, 2 submitters; last evaluated 2024-12-18). AlphaMissense: likely pathogenic (0.9962); Very rare (popmax 0.00399%, nfe); Associated with autosomal recessive nonsyndromic hearing loss 7.

What condition is associated with TMC1 p.Ser208Arg (c.624C>A)?

TMC1 p.Ser208Arg (c.624C>A) is associated with autosomal recessive nonsyndromic hearing loss 7, autosomal dominant nonsyndromic hearing loss 36 (ClinVar).

How common is TMC1 p.Ser208Arg (c.624C>A) in the general population?

TMC1 p.Ser208Arg (c.624C>A) is very rare (popmax 0.00399%, nfe) (gnomAD).

What do computational predictors say about TMC1 p.Ser208Arg (c.624C>A)?

AlphaMissense predicts likely pathogenic (score 0.9962) — an in-silico prediction, not a clinical call.

TMC1 p.Ser208Arg

c.624C>A · rs781747541 · VCV417922

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9962 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00399%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autosomal recessive nonsyndromic hearing loss 7

Computational evidence

Protein change
AlphaMissense	0.9962	likely pathogenic · top 4% in TMC1
REVEL	0.279	benign-leaning
SaProt	LLR -12.00	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.79	GERP 0.56, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 187 kb · p 0.0013 · regional, not allelic
Overall
CADD	22.3	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00399% European (non-Finnish) · 47/1,176,758 alleles

Filtering AF 0.00308% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00276%

Overall 0.0035% 51/1,458,060 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00399%	25,037
Remaining individualsnot grpmax-eligible	0.0032%	31,207
African / African-American	0.00133%	74,924
South Asian	0.0011%	91,012

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.Ser208Arg
Coding: c.624C>A
MANE Select: NM_138691
dbSNP: rs781747541
Type: single nucleotide variant
Location: chr9:72751938 (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 recessive nonsyndromic hearing loss 7 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: autosomal dominant nonsyndromic hearing loss 36

Similar variants

TMC1 p.Ser208Gly Uncertain significance ★ ⚠ 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
TMC1 p.Arg264Ter 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-ser208arg (accessed [today's date]).

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