Is TMC8 p.Ser389= (c.1167C>T) pathogenic?

TMC8 p.Ser389= (c.1167C>T) is classified Likely benign in TMC8 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-24). Ultra-rare (popmax 0.0986%, mid); Associated with epidermodysplasia verruciformis.

What condition is associated with TMC8 p.Ser389= (c.1167C>T)?

TMC8 p.Ser389= (c.1167C>T) is associated with epidermodysplasia verruciformis (ClinVar).

How common is TMC8 p.Ser389= (c.1167C>T) in the general population?

TMC8 p.Ser389= (c.1167C>T) is ultra-rare (popmax 0.0986%, mid) (gnomAD).

How is Inherited epidermodysplasia verruciformis inherited?

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

TMC8 p.Ser389=

c.1167C>T · rs750054783 · VCV750114

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0986%, mid)

Conditions

epidermodysplasia verruciformis

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.30	donor loss, 49 bp away · masked 0 · deltas
Pangolin	Δ0.35	loss · gain 0.01 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 0.46	GERP 0.55, phastCons 0.4
Overall
CADD	9.194	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0986% Middle Eastern · 6/6,084 alleles

Filtering AF 0.0429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0293%

Overall 0.00297% 48/1,613,842 alleles · ultra-rare exomes 47/1,461,680 · genomes 1/152,162 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0986%	1,014
East Asian	0.02%	4,988
South Asian	0.0132%	7,591
African / African-American	0.00667%	14,982
Remaining individualsnot grpmax-eligible	0.0064%	15,620
Admixed American	0.00167%	59,994
European (non-Finnish)	0.000932%	107,272

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.Ser389=
Coding: c.1167C>T
MANE Select: NM_152468
dbSNP: rs750054783
Type: single nucleotide variant
Location: chr17:78137274 (GRCh38)
Gene constraint: LOEUF 1.201 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 76.77
Residue 389: the 'tmc domain' 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 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
TMC8 p.Ala345Thr 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-ser389 (accessed [today's date]).

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