Is TMC6 p.Pro659= (c.1977C>T) pathogenic?

TMC6 p.Pro659= (c.1977C>T) is classified Likely benign in TMC6 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-26). Very rare (popmax 0.00554%, sas); Associated with epidermodysplasia verruciformis.

What condition is associated with TMC6 p.Pro659= (c.1977C>T)?

TMC6 p.Pro659= (c.1977C>T) is associated with epidermodysplasia verruciformis (ClinVar).

How common is TMC6 p.Pro659= (c.1977C>T) in the general population?

TMC6 p.Pro659= (c.1977C>T) is very rare (popmax 0.00554%, sas) (gnomAD).

How is Inherited epidermodysplasia verruciformis inherited?

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

TMC6 p.Pro659=

c.1977C>T · rs567036907 · VCV2772447

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00554%, sas)

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 Δ0.58 · evaluated, not missing
Constraint at this position
Conservation	phyloP -3	GERP -2.9
Overall
CADD	6.877	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00554% South Asian · 5/90,174 alleles

Filtering AF 0.00212% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00138%

Overall 0.00155% 25/1,608,172 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00554%	18,035
East Asian	0.00447%	22,352
African / African-American	0.00267%	37,503
Remaining individualsnot grpmax-eligible	0.00161%	62,266
European (non-Finnish)	0.00127%	78,502

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.Pro659=
Coding: c.1977C>T
MANE Select: NM_001127198
dbSNP: rs567036907
Type: single nucleotide variant
Location: chr17:78117846 (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.Pro659_Phe661dup Uncertain significance ★ same residue
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

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-pro659 (accessed [today's date]).

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