Is TMC8 p.Lys403fs (c.1207_1208del) pathogenic?

TMC8 p.Lys403fs (c.12071208del) is classified Pathogenic in TMC8 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-10). Very rare (popmax 0.00133%, afr); Associated with epidermodysplasia verruciformis.

What condition is associated with TMC8 p.Lys403fs (c.1207_1208del)?

TMC8 p.Lys403fs (c.1207_1208del) is associated with epidermodysplasia verruciformis (ClinVar).

How common is TMC8 p.Lys403fs (c.1207_1208del) in the general population?

TMC8 p.Lys403fs (c.1207_1208del) is very rare (popmax 0.00133%, afr) (gnomAD).

How is Inherited epidermodysplasia verruciformis inherited?

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

TMC8 p.Lys403fs

c.1207_1208del · rs2510806153 · VCV1954704

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Conditions

epidermodysplasia verruciformis

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 10 of 16
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 3.1	GERP 0.55, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/75,026 alleles

Filtering AF 0.000615% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000474%

Overall 0.000867% 14/1,614,016 alleles · very rare exomes 14/1,461,708 · genomes 0/152,308 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	75,026
European (non-Finnish)	0.0011%	90,770

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.Lys403fs
Coding: c.1207_1208del
MANE Select: NM_152468
dbSNP: rs2510806153
Type: Deletion
Location: chr17:78137314 (GRCh38)
Gene constraint: LOEUF 1.201 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 76.77
Residue 403: 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.Lys403= Benign ★★ same residue
TMC8 p.Lys403Asn Uncertain significance ★ ⚠ same residue
TMC8 p.Arg295fs Pathogenic ★★ same condition
TMC8 p.Ala188fs Pathogenic ★ same condition
TMC8 p.Asp142fs Pathogenic ★ same condition
TMC8 p.Asp251fs Pathogenic ★ same condition
TMC8 p.Gln236fs Pathogenic ★ same condition
TMC8 p.Gln291fs 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/tmc8-p-lys403fs (accessed [today's date]).

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