Is TMC8 p.Pro721= (c.2163C>T) pathogenic?

TMC8 p.Pro721= (c.2163C>T) is classified Likely benign in TMC8 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-16). Very rare (popmax 0.00347%, amr); Associated with epidermodysplasia verruciformis.

What condition is associated with TMC8 p.Pro721= (c.2163C>T)?

TMC8 p.Pro721= (c.2163C>T) is associated with epidermodysplasia verruciformis (ClinVar).

How common is TMC8 p.Pro721= (c.2163C>T) in the general population?

TMC8 p.Pro721= (c.2163C>T) is very rare (popmax 0.00347%, amr) (gnomAD).

How is Inherited epidermodysplasia verruciformis inherited?

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

TMC8 p.Pro721=

c.2163C>T · rs527688678 · VCV1619589

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00347%, 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 -0.055	GERP 1.7, phastCons 0.3
Overall
CADD	5.532	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00347% Admixed American · 2/57,614 alleles

Filtering AF 0.0021% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00185%

Overall 0.00247% 39/1,577,476 alleles · very rare exomes 33/1,425,250 · genomes 6/152,226 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00347%	28,807
European (non-Finnish)	0.00291%	34,326
African / African-American	0.0027%	37,055
Finnishnot grpmax-eligible	0.00191%	52,326

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.Pro721=
Coding: c.2163C>T
MANE Select: NM_152468
dbSNP: rs527688678
Type: single nucleotide variant
Location: chr17:78141094 (GRCh38)
Gene constraint: LOEUF 1.201 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 76.77
Residue 721: the 'disordered' region; 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.Pro721Ala Uncertain significance ★ ⚠ same residue
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
TMC8 p.Ala188Val Uncertain significance ★★ ⚠ same condition
TMC8 p.Ala290Thr Uncertain significance ★★ ⚠ same condition
TMC8 p.Ala313Val Uncertain significance ★★ ⚠ same condition
TMC8 p.Ala316Thr 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/tmc8-p-pro721 (accessed [today's date]).

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