Is TMC8 p.Leu385Phe (c.1155G>T) pathogenic?

TMC8 p.Leu385Phe (c.1155G>T) is classified Uncertain significance in TMC8 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-12-20). AlphaMissense: ambiguous (0.3594); Very rare (popmax 0.005%, amr); Associated with epidermodysplasia verruciformis.

What condition is associated with TMC8 p.Leu385Phe (c.1155G>T)?

TMC8 p.Leu385Phe (c.1155G>T) is associated with epidermodysplasia verruciformis (ClinVar).

How common is TMC8 p.Leu385Phe (c.1155G>T) in the general population?

TMC8 p.Leu385Phe (c.1155G>T) is very rare (popmax 0.005%, amr) (gnomAD).

How is Inherited epidermodysplasia verruciformis inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about TMC8 p.Leu385Phe (c.1155G>T)?

AlphaMissense predicts ambiguous (score 0.3594) — an in-silico prediction, not a clinical call.

TMC8 p.Leu385Phe

c.1155G>T · rs1057423570 · VCV2059146

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3594 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Conditions

epidermodysplasia verruciformis

Computational evidence

Protein change
AlphaMissense	0.3594	ambiguous
REVEL	0.362	indeterminate
SaProt	LLR -6.46	tolerated
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>A here scores Δ0.33 · evaluated, not missing
Constraint at this position
Conservation	phyloP 1.7	GERP 0.6, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 9,520 bp · p 0.44 · regional, not allelic
Overall
CADD	23.0	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

Grpmax group 0.005% Admixed American · 3/59,996 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.000248% 4/1,613,802 alleles · very rare exomes 4/1,461,616 · genomes 0/152,186 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.005%	19,999
Remaining individualsnot grpmax-eligible	0.0016%	62,474

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.Leu385Phe
Coding: c.1155G>T
MANE Select: NM_152468
dbSNP: rs1057423570
Type: single nucleotide variant
Location: chr17:78137262 (GRCh38)
Gene constraint: LOEUF 1.201 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 76.77
Residue 385: the 'tmc domain' region; a UniProt-annotated variant site (in ev2)

Full TMC8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

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

For Inherited epidermodysplasia verruciformis (Orphanet):

Inheritance: Autosomal recessive
Onset: All ages

Similar variants

TMC8 p.Leu385= Likely benign ★ same residue
TMC8 c.1824-1G>C Pathogenic/Likely pathogenic ★★ same condition
TMC8 c.449-1G>T Likely pathogenic ★★ same condition
TMC8 p.Arg190Ter Pathogenic ★★ same condition
TMC8 p.Ala188Val Uncertain significance ★★ ⚠ same condition
TMC8 p.Ala290Thr Uncertain significance ★★ ⚠ same condition
TMC8 p.Ala313Val Uncertain significance ★★ ⚠ same condition
TMC8 p.Ala316Thr 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/tmc8-p-leu385phe (accessed [today's date]).

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