Is TMC8 p.Leu583fs (c.1746del) pathogenic?

TMC8 p.Leu583fs (c.1746del) is classified Pathogenic in TMC8 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-02-10). Very rare (popmax 0.00167%, amr); Associated with epidermodysplasia verruciformis.

What condition is associated with TMC8 p.Leu583fs (c.1746del)?

TMC8 p.Leu583fs (c.1746del) is associated with epidermodysplasia verruciformis (ClinVar).

How common is TMC8 p.Leu583fs (c.1746del) in the general population?

TMC8 p.Leu583fs (c.1746del) is very rare (popmax 0.00167%, amr) (gnomAD).

How is Inherited epidermodysplasia verruciformis inherited?

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

TMC8 p.Leu583fs

c.1746del · rs1598923748 · VCV658615

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Conditions

epidermodysplasia verruciformis

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 14 of 16
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.013	GERP -2.8, phastCons 0.002

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/60,026 alleles

Overall 6.2e-05% 1/1,613,858 alleles · very rare exomes 1/1,461,498 · genomes 0/152,360 · joint denominator

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.Leu583fs
Coding: c.1746del
MANE Select: NM_152468
dbSNP: rs1598923748
Type: Deletion
Location: chr17:78138653 (GRCh38)
Gene constraint: LOEUF 1.201 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 76.77
Residue 583: 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.Arg295fs Pathogenic ★★ same condition
TMC8 p.Ala188fs Pathogenic ★ same condition
TMC8 p.Asp142fs Pathogenic ★ same condition
TMC8 p.Asp251fs Pathogenic ★ same condition
TMC8 p.Gln236fs Pathogenic ★ same condition
TMC8 p.Gln291fs Pathogenic ★ same condition
TMC8 p.Glu425fs Pathogenic ★ same condition
TMC8 p.Leu300fs Pathogenic ★ 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-leu583fs (accessed [today's date]).

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