Is TMC6 p.Ser222= (c.666C>T) pathogenic?

TMC6 p.Ser222= (c.666C>T) is classified Benign/Likely benign in TMC6 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-18). Rare (popmax 0.181%, afr); Associated with epidermodysplasia verruciformis.

What condition is associated with TMC6 p.Ser222= (c.666C>T)?

TMC6 p.Ser222= (c.666C>T) is associated with epidermodysplasia verruciformis (ClinVar).

How common is TMC6 p.Ser222= (c.666C>T) in the general population?

TMC6 p.Ser222= (c.666C>T) is rare (popmax 0.181%, afr) (gnomAD).

How is Inherited epidermodysplasia verruciformis inherited?

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

TMC6 p.Ser222=

c.666C>T · rs371379212 · VCV721828

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

rare (popmax 0.181%, afr)

Conditions

epidermodysplasia verruciformis

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.64 · evaluated, not missing
Pangolin	Δ0.20	gain · loss 0.04 · SpliceAI below 0.2 · independent
Constraint at this position
Conservation	phyloP -13	GERP -2
Overall
CADD	0.977	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.181% African / African-American · 135/74,510 alleles

Filtering AF 0.156% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.147%

Overall 0.0156% 247/1,584,606 alleles · rare exomes 142/1,432,258 · genomes 105/152,348 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.181%	552
Ashkenazi Jewishnot grpmax-eligible	0.0722%	1,385
Remaining individualsnot grpmax-eligible	0.0326%	3,069
Admixed American	0.0255%	3,929
Finnishnot grpmax-eligible	0.00987%	10,135
East Asian	0.00925%	10,813
European (non-Finnish)	0.00394%	25,349
South Asian	0.00114%	87,788

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.Ser222=
Coding: c.666C>T
MANE Select: NM_001127198
dbSNP: rs371379212
Type: single nucleotide variant
Location: chr17:78124749 (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-ser222 (accessed [today's date]).

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