Is TMC6 p.Phe658Val (c.1972T>G) pathogenic?

TMC6 p.Phe658Val (c.1972T>G) is classified Uncertain significance in TMC6 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-07-13). AlphaMissense: likely benign (0.1517); Very rare (popmax 0.00017%, nfe); Associated with epidermodysplasia verruciformis, susceptibility to, 1.

What condition is associated with TMC6 p.Phe658Val (c.1972T>G)?

TMC6 p.Phe658Val (c.1972T>G) is associated with epidermodysplasia verruciformis, susceptibility to, 1 (ClinVar).

How common is TMC6 p.Phe658Val (c.1972T>G) in the general population?

TMC6 p.Phe658Val (c.1972T>G) is very rare (popmax 0.00017%, nfe) (gnomAD).

What do computational predictors say about TMC6 p.Phe658Val (c.1972T>G)?

AlphaMissense predicts likely benign (score 0.1517) — an in-silico prediction, not a clinical call.

TMC6 p.Phe658Val

c.1972T>G · rs1280636115 · VCV656239

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1517 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

epidermodysplasia verruciformis, susceptibility to, 1

Computational evidence

Protein change
AlphaMissense	0.1517	likely benign
REVEL	0.511	indeterminate
SaProt	LLR -10.07	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.4, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 14 kb · p 0.88 · regional, not allelic
Overall
CADD	24.9	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 0.00017% European (non-Finnish) · 2/1,177,638 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,455,978 alleles · very rare

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: TMC6
Protein: p.Phe658Val
Coding: c.1972T>G
MANE Select: NM_001127198
dbSNP: rs1280636115
Type: single nucleotide variant
Location: chr17:78117851 (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

epidermodysplasia verruciformis, susceptibility to, 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TMC6 p.Arg94Ter Pathogenic ★★ same condition
TMC6 p.Arg785Thr Uncertain significance ★★ ⚠ same condition
TMC6 p.Phe366Cys Uncertain significance ★★ ⚠ same condition
TMC6 p.Thr392Met Uncertain significance ★★ ⚠ same condition
TMC6 p.Tyr25His Uncertain significance ★★ ⚠ same condition
TMC6 p.Lys235Arg Benign/Likely benign ★★ same condition
TMC6 c.892-2A>T Pathogenic ★ same condition
TMC6 p.Tyr248Ter 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/tmc6-p-phe658val (accessed [today's date]).

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