Is TMC6 p.Phe557= (c.1671C>T) pathogenic?

TMC6 p.Phe557= (c.1671C>T) is classified Likely benign in TMC6 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-07). Very rare (popmax 0.00333%, amr); Associated with epidermodysplasia verruciformis.

What condition is associated with TMC6 p.Phe557= (c.1671C>T)?

TMC6 p.Phe557= (c.1671C>T) is associated with epidermodysplasia verruciformis (ClinVar).

How common is TMC6 p.Phe557= (c.1671C>T) in the general population?

TMC6 p.Phe557= (c.1671C>T) is very rare (popmax 0.00333%, amr) (gnomAD).

How is Inherited epidermodysplasia verruciformis inherited?

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

TMC6 p.Phe557=

c.1671C>T · rs765210208 · VCV2740162

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Conditions

epidermodysplasia verruciformis

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.36	GERP -2.8, phastCons 0.008
Overall
CADD	8.333	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00333% Admixed American · 2/59,984 alleles

Filtering AF 0.000803% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00065%

Overall 0.0013% 21/1,613,876 alleles · very rare exomes 20/1,461,722 · genomes 1/152,154 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	29,992
Remaining individualsnot grpmax-eligible	0.0016%	62,482
European (non-Finnish)	0.00136%	73,752
African / African-American	0.00133%	74,914
South Asian	0.0011%	91,086

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.Phe557=
Coding: c.1671C>T
MANE Select: NM_001127198
dbSNP: rs765210208
Type: single nucleotide variant
Location: chr17:78120697 (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.Arg94Ter Pathogenic ★★ same condition
TMC6 c.1383+4C>T Uncertain significance ★★ same condition
TMC6 p.Ala124Pro Uncertain significance ★★ ⚠ same condition
TMC6 p.Ala212Val Uncertain significance ★★ ⚠ same condition
TMC6 p.Ala233Thr Uncertain significance ★★ ⚠ same condition
TMC6 p.Ala380Thr Uncertain significance ★★ ⚠ same condition
TMC6 p.Ala432Val Uncertain significance ★★ ⚠ same condition
TMC6 p.Ala495Thr 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/tmc6-p-phe557 (accessed [today's date]).

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