Is TMC8 p.Leu628Pro (c.1883T>C) pathogenic?

TMC8 p.Leu628Pro (c.1883T>C) is classified Uncertain significance in TMC8 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-11-23). AlphaMissense: likely pathogenic (0.8509); Very rare (popmax 8.47e-05%, nfe); Associated with epidermodysplasia verruciformis.

What condition is associated with TMC8 p.Leu628Pro (c.1883T>C)?

TMC8 p.Leu628Pro (c.1883T>C) is associated with epidermodysplasia verruciformis (ClinVar).

How common is TMC8 p.Leu628Pro (c.1883T>C) in the general population?

TMC8 p.Leu628Pro (c.1883T>C) is very rare (popmax 8.47e-05%, nfe) (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.Leu628Pro (c.1883T>C)?

AlphaMissense predicts likely pathogenic (score 0.8509) — an in-silico prediction, not a clinical call.

TMC8 p.Leu628Pro

c.1883T>C · rs2145722630 · VCV1465147

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8509 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

epidermodysplasia verruciformis

Computational evidence

Protein change
AlphaMissense	0.8509	likely pathogenic · top 5% in TMC8
REVEL	0.865	moderately pathogenic-leaning
SaProt	LLR -14.48	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.4	GERP 1.4, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 9,520 bp · p 0.44 · regional, not allelic
Overall
CADD	29.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 8.47e-05% European (non-Finnish) · 1/1,180,020 alleles

Overall 6.2e-05% 1/1,613,598 alleles · very rare exomes 1/1,461,336 · genomes 0/152,262 · 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.Leu628Pro
Coding: c.1883T>C
MANE Select: NM_152468
dbSNP: rs2145722630
Type: single nucleotide variant
Location: chr17:78139221 (GRCh38)
Gene constraint: LOEUF 1.201 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 76.77
Residue 628: 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 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
TMC8 p.Ala345Thr 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-leu628pro (accessed [today's date]).

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