Is TMC6 p.Phe351fs (c.1053_1056del) pathogenic?

TMC6 p.Phe351fs (c.10531056del) is classified Pathogenic in TMC6 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-02-08). Very rare (popmax 0.000593%, nfe); Associated with epidermodysplasia verruciformis.

What condition is associated with TMC6 p.Phe351fs (c.1053_1056del)?

TMC6 p.Phe351fs (c.1053_1056del) is associated with epidermodysplasia verruciformis (ClinVar).

How common is TMC6 p.Phe351fs (c.1053_1056del) in the general population?

TMC6 p.Phe351fs (c.1053_1056del) is very rare (popmax 0.000593%, nfe) (gnomAD).

How is Inherited epidermodysplasia verruciformis inherited?

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

TMC6 p.Phe351fs

c.1053_1056del · rs2510624241 · VCV1921332

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000593%, nfe)

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 9 of 20
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -3.3	GERP -3.1

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000593% European (non-Finnish) · 7/1,179,982 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000434% 7/1,613,790 alleles · very rare exomes 7/1,461,536 · genomes 0/152,254 · 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: TMC6
Protein: p.Phe351fs
Coding: c.1053_1056del
MANE Select: NM_001127198
dbSNP: rs2510624241
Type: Deletion
Location: chr17:78124015 (GRCh38)
Gene constraint: LOEUF 1.019 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 72.56

Full TMC6 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

TMC6 p.Leu323fs Pathogenic/Likely pathogenic ★★ same condition
TMC6 c.1716-6del Benign ★★ same condition
TMC6 c.536+14del Likely benign ★★ same condition
TMC6 c.363_430+80del Likely pathogenic ★ same condition
TMC6 p.Asp388fs Pathogenic ★ same condition
TMC6 p.Ile237fs Pathogenic ★ same condition
TMC6 p.Met648fs Pathogenic ★ same condition
TMC6 p.Phe566fs 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/tmc6-p-phe351fs (accessed [today's date]).

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