Is TMC8 p.Phe534del (c.1594TTC[2]) pathogenic?

TMC8 p.Phe534del (c.1594TTC[2]) is classified Uncertain significance in TMC8 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-14). Very rare (popmax 0.000254%, nfe); Associated with epidermodysplasia verruciformis.

What condition is associated with TMC8 p.Phe534del (c.1594TTC[2])?

TMC8 p.Phe534del (c.1594TTC[2]) is associated with epidermodysplasia verruciformis (ClinVar).

How common is TMC8 p.Phe534del (c.1594TTC[2]) in the general population?

TMC8 p.Phe534del (c.1594TTC[2]) is very rare (popmax 0.000254%, nfe) (gnomAD).

How is Inherited epidermodysplasia verruciformis inherited?

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

TMC8 p.Phe534del

c.1594TTC[2] · rs1176579021 · VCV1473871

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Conditions

epidermodysplasia verruciformis

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 3.1	GERP -0.54, phastCons 1

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000254% European (non-Finnish) · 3/1,179,996 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000186% 3/1,612,728 alleles · very rare exomes 3/1,460,384 · genomes 0/152,344 · 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.Phe534del
Coding: c.1594TTC[2]
MANE Select: NM_152468
dbSNP: rs1176579021
Type: Microsatellite
Location: chr17:78138408 (GRCh38)
Gene constraint: LOEUF 1.201 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 76.77
Residue 534: 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.Leu221fs Pathogenic ★ same condition
TMC8 p.Leu233fs Pathogenic ★ same condition
TMC8 c.1664+15_1664+17del Likely benign ★ same condition
TMC8 c.1903-7_1903-5del Likely benign ★ same condition
TMC8 c.816+16_816+19del Likely benign ★ same condition
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

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-phe534del (accessed [today's date]).

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