Is TMC8 p.Phe355Leu (c.1065C>G) pathogenic?

TMC8 p.Phe355Leu (c.1065C>G) is classified Uncertain significance in TMC8 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-08-10). AlphaMissense: likely pathogenic (0.9095); Ultra-rare (popmax 0.0988%, sas); Associated with epidermodysplasia verruciformis, susceptibility to, 1.

What condition is associated with TMC8 p.Phe355Leu (c.1065C>G)?

TMC8 p.Phe355Leu (c.1065C>G) is associated with epidermodysplasia verruciformis, susceptibility to, 1 (ClinVar).

How common is TMC8 p.Phe355Leu (c.1065C>G) in the general population?

TMC8 p.Phe355Leu (c.1065C>G) is ultra-rare (popmax 0.0988%, sas) (gnomAD).

What do computational predictors say about TMC8 p.Phe355Leu (c.1065C>G)?

AlphaMissense predicts likely pathogenic (score 0.9095) — an in-silico prediction, not a clinical call.

TMC8 p.Phe355Leu

c.1065C>G · rs760559122 · VCV651874

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9095 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0988%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

epidermodysplasia verruciformis, susceptibility to, 1

Computational evidence

Protein change
AlphaMissense	0.9095	likely pathogenic · top 3% in TMC8
REVEL	0.405	indeterminate
SaProt	LLR -8.53	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.3	GERP -3.4
Regional constraint	o/e 0.97	unconstrained · MANE · 9,520 bp · p 0.44 · regional, not allelic
Overall
CADD	11.58	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 0.0988% South Asian · 90/91,078 alleles

Filtering AF 0.0823% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0761%

Overall 0.00582% 94/1,614,042 alleles · ultra-rare exomes 88/1,461,862 · genomes 6/152,180 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0988%	1,012
Remaining individualsnot grpmax-eligible	0.0048%	20,830
Admixed American	0.00167%	60,002

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: TMC8
Protein: p.Phe355Leu
Coding: c.1065C>G
MANE Select: NM_152468
dbSNP: rs760559122
Type: single nucleotide variant
Location: chr17:78134947 (GRCh38)
Gene constraint: LOEUF 1.201 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 76.77

Full TMC8 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

TMC8 c.1665-8C>G Uncertain significance ★ same condition
TMC8 p.Ala442Val Uncertain significance ★ ⚠ same condition
TMC8 p.Arg455Gln Conflicting classifications of pathogenicity ★ ⚠ same condition
TMC8 p.Asp402Glu Uncertain significance ★ ⚠ same condition
TMC8 p.Gly707Glu Uncertain significance ★ ⚠ same condition
TMC8 p.Pro661Leu Conflicting classifications of pathogenicity ★ ⚠ same condition
TMC8 p.Pro721Ala Uncertain significance ★ ⚠ same condition
TMC8 p.Val390Ile Conflicting classifications of pathogenicity ★ ⚠ 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/tmc8-p-phe355leu (accessed [today's date]).

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