Is TMC8 p.Leu90Phe (c.268C>T) pathogenic?

TMC8 p.Leu90Phe (c.268C>T) is classified Uncertain significance in TMC8 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-01). AlphaMissense: likely benign (0.1436); Ultra-rare (popmax 0.0234%, afr); Associated with epidermodysplasia verruciformis.

What condition is associated with TMC8 p.Leu90Phe (c.268C>T)?

TMC8 p.Leu90Phe (c.268C>T) is associated with epidermodysplasia verruciformis (ClinVar).

How common is TMC8 p.Leu90Phe (c.268C>T) in the general population?

TMC8 p.Leu90Phe (c.268C>T) is ultra-rare (popmax 0.0234%, afr) (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.Leu90Phe (c.268C>T)?

AlphaMissense predicts likely benign (score 0.1436) — an in-silico prediction, not a clinical call.

TMC8 p.Leu90Phe

c.268C>T · rs1222174878 · VCV640900

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1436 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0234%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

epidermodysplasia verruciformis

⚠ Built without this gene's context — gene constraint and dosage, protein structure, pathways, panels and related-variant links were not looked up for this page. why

Computational evidence

Protein change
AlphaMissense	0.1436	likely benign
REVEL	0.496	indeterminate
SaProt	LLR -8.41	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 3.6	GERP 1.2, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 9,520 bp · p 0.44 · regional, not allelic
Overall
CADD	25.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0234% African / African-American · 17/72,780 alleles

Filtering AF 0.0149% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0122%

Overall 0.00111% 17/1,531,858 alleles · ultra-rare exomes 6/1,379,640 · genomes 11/152,218 · joint denominator

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.Leu90Phe
Coding: c.268C>T
MANE Select: NM_152468
dbSNP: rs1222174878
Type: single nucleotide variant
Location: chr17:78132000 (GRCh38)

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

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-leu90phe (accessed [today's date]).

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