Is TMC1 p.Phe207Ile (c.619T>A) pathogenic?

TMC1 p.Phe207Ile (c.619T>A) is classified Uncertain significance in TMC1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-05-08). AlphaMissense: ambiguous (0.4552); Ultra-rare (popmax 0.0347%, afr); Associated with TMC1-related disorder.

What condition is associated with TMC1 p.Phe207Ile (c.619T>A)?

TMC1 p.Phe207Ile (c.619T>A) is associated with TMC1-related disorder (ClinVar).

How common is TMC1 p.Phe207Ile (c.619T>A) in the general population?

TMC1 p.Phe207Ile (c.619T>A) is ultra-rare (popmax 0.0347%, afr) (gnomAD).

What do computational predictors say about TMC1 p.Phe207Ile (c.619T>A)?

AlphaMissense predicts ambiguous (score 0.4552) — an in-silico prediction, not a clinical call.

TMC1 p.Phe207Ile

c.619T>A · rs368042336 · VCV1990176

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.4552 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0347%, afr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

TMC1-related disorder

Computational evidence

Protein change
AlphaMissense	0.4552	ambiguous
REVEL	0.182	moderately benign-leaning
SaProt	LLR -9.79	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.1	GERP 2.3, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 187 kb · p 0.0013 · regional, not allelic
Overall
CADD	26.4	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 0.0347% African / African-American · 26/74,874 alleles

Filtering AF 0.0243% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0208%

Overall 0.00174% 28/1,611,928 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0347%	2,880
Remaining individualsnot grpmax-eligible	0.0032%	31,223

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.Phe207Ile
Coding: c.619T>A
MANE Select: NM_138691
dbSNP: rs368042336
Type: single nucleotide variant
Location: chr9:72751933 (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

TMC1-related disorder

Similar variants

TMC1 c.236+1G>A Pathogenic ★★ same condition
TMC1 p.Arg34Ter Pathogenic ★★ same condition
TMC1 p.Arg604Ter Pathogenic ★★ same condition
TMC1 p.Asp572Asn Pathogenic/Likely pathogenic ★★ ⚠ same condition
TMC1 p.Asp572His Pathogenic/Likely pathogenic ★★ ⚠ same condition
TMC1 p.Asp684His Pathogenic/Likely pathogenic ★★ same condition
TMC1 p.Trp111Ter Pathogenic/Likely pathogenic ★★ same condition
TMC1 p.Tyr215Ter Pathogenic/Likely 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-phe207ile (accessed [today's date]).

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