Is TMC1 p.Phe419Ser (c.1256T>C) pathogenic?

TMC1 p.Phe419Ser (c.1256T>C) is classified Uncertain significance in TMC1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-06-18). AlphaMissense: likely pathogenic (0.8894); Very rare (popmax 0.000424%, nfe); Associated with autosomal dominant nonsyndromic hearing loss 36.

What condition is associated with TMC1 p.Phe419Ser (c.1256T>C)?

TMC1 p.Phe419Ser (c.1256T>C) is associated with autosomal dominant nonsyndromic hearing loss 36 (ClinVar).

How common is TMC1 p.Phe419Ser (c.1256T>C) in the general population?

TMC1 p.Phe419Ser (c.1256T>C) is very rare (popmax 0.000424%, nfe) (gnomAD).

What do computational predictors say about TMC1 p.Phe419Ser (c.1256T>C)?

AlphaMissense predicts likely pathogenic (score 0.8894) — an in-silico prediction, not a clinical call.

TMC1 p.Phe419Ser

c.1256T>C · rs760645934 · VCV1895419

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8894 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autosomal dominant nonsyndromic hearing loss 36

Computational evidence

Protein change
AlphaMissense	0.8894	likely pathogenic
REVEL	0.832	moderately pathogenic-leaning
SaProt	LLR -9.43	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.3, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 187 kb · p 0.0013 · regional, not allelic
Overall
CADD	29.4	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 0.000424% European (non-Finnish) · 5/1,179,948 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.00031% 5/1,613,458 alleles · very rare exomes 5/1,461,094 · genomes 0/152,364 · joint denominator

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.Phe419Ser
Coding: c.1256T>C
MANE Select: NM_138691
dbSNP: rs760645934
Type: single nucleotide variant
Location: chr9:72791917 (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

Similar variants

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 p.Arg34Ter Pathogenic ★★ same condition
TMC1 p.Arg389Gln Pathogenic/Likely pathogenic ★★ same condition
TMC1 p.Arg389Ter Pathogenic ★★ same condition
TMC1 p.Arg512Ter Pathogenic ★★ same condition
TMC1 p.Arg604Ter 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-phe419ser (accessed [today's date]).

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