Is TMC1 p.Ser414Pro (c.1240T>C) pathogenic?

TMC1 p.Ser414Pro (c.1240T>C) is classified Uncertain significance in TMC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-02). AlphaMissense: likely pathogenic (0.9908); Very rare (popmax 0.00267%, afr).

How common is TMC1 p.Ser414Pro (c.1240T>C) in the general population?

TMC1 p.Ser414Pro (c.1240T>C) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about TMC1 p.Ser414Pro (c.1240T>C)?

AlphaMissense predicts likely pathogenic (score 0.9908) — an in-silico prediction, not a clinical call.

TMC1 p.Ser414Pro

c.1240T>C · VCV4527487

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9908 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9908	likely pathogenic · top 8% in TMC1
REVEL	0.937	strongly pathogenic-leaning
SaProt	LLR -15.12	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
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	28.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00267% African / African-American · 2/74,896 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000124% 2/1,612,494 alleles · very rare exomes 1/1,460,328 · genomes 1/152,166 · 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.Ser414Pro
Coding: c.1240T>C
MANE Select: NM_138691
Type: single nucleotide variant
Location: chr9:72791901 (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

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-ser414pro (accessed [today's date]).

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