Is TMC8 p.Ser422fs (c.1263del) pathogenic?

TMC8 p.Ser422fs (c.1263del) is classified Pathogenic in TMC8 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-19). Associated with epidermodysplasia verruciformis.

What condition is associated with TMC8 p.Ser422fs (c.1263del)?

TMC8 p.Ser422fs (c.1263del) is associated with epidermodysplasia verruciformis (ClinVar).

How is Inherited epidermodysplasia verruciformis inherited?

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

TMC8 p.Ser422fs

c.1263del · VCV4730718

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

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 11 of 16
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 3.3	GERP -2.1, phastCons 0.98

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

Variant & gene context

Gene: TMC8
Protein: p.Ser422fs
Coding: c.1263del
MANE Select: NM_152468
Type: Deletion
Location: chr17:78137728 (GRCh38)
Gene constraint: LOEUF 1.201 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 76.77
Residue 422: 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.Ser422= Likely benign ★★ 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
TMC8 p.Glu425fs 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-ser422fs (accessed [today's date]).

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