Is TMC6 p.Phe269Val (c.805T>G) pathogenic?

TMC6 p.Phe269Val (c.805T>G) is classified Uncertain significance in TMC6 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-03). AlphaMissense: likely benign (0.2465); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with TMC6 p.Phe269Val (c.805T>G)?

TMC6 p.Phe269Val (c.805T>G) is associated with Inborn genetic diseases (ClinVar).

How common is TMC6 p.Phe269Val (c.805T>G) in the general population?

TMC6 p.Phe269Val (c.805T>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TMC6 p.Phe269Val (c.805T>G)?

AlphaMissense predicts likely benign (score 0.2465) — an in-silico prediction, not a clinical call.

TMC6 p.Phe269Val

c.805T>G · VCV3969650

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2465 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2465	likely benign
REVEL	0.522	indeterminate
SaProt	LLR -11.71	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 5	GERP 0.23, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 14 kb · p 0.88 · regional, not allelic
Overall
CADD	22.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: TMC6
Protein: p.Phe269Val
Coding: c.805T>G
MANE Select: NM_001127198
Type: single nucleotide variant
Location: chr17:78124610 (GRCh38)
Gene constraint: LOEUF 1.019 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 72.56

Full TMC6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TMC6 p.Ala794Pro Uncertain significance ★★ ⚠ same condition
TMC6 p.Arg109Trp Uncertain significance ★★ ⚠ same condition
TMC6 p.Arg122Pro Uncertain significance ★★ ⚠ same condition
TMC6 p.Arg161Trp Uncertain significance ★★ ⚠ same condition
TMC6 p.Arg591Trp Uncertain significance ★★ ⚠ same condition
TMC6 p.Arg747Cys Uncertain significance ★★ ⚠ same condition
TMC6 p.Arg80Cys Uncertain significance ★★ ⚠ same condition
TMC6 p.Arg88Cys Uncertain significance ★★ ⚠ 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/tmc6-p-phe269val (accessed [today's date]).

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