Is TMC1 p.Arg74fs (c.215_219dup) pathogenic?

TMC1 p.Arg74fs (c.215219dup) is classified Pathogenic in TMC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2013-11-26). Absent from gnomAD; Associated with Rare genetic deafness.

What condition is associated with TMC1 p.Arg74fs (c.215_219dup)?

TMC1 p.Arg74fs (c.215_219dup) is associated with Rare genetic deafness (ClinVar).

How common is TMC1 p.Arg74fs (c.215_219dup) in the general population?

TMC1 p.Arg74fs (c.215_219dup) is absent from gnomAD (gnomAD).

TMC1 p.Arg74fs

c.215_219dup · rs730880359 · VCV179431

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Not reported

no gnomAD frequency available for this variant

Conditions

Rare genetic deafness

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 7 of 24
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 5.5	GERP 0.65, phastCons 1

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

Population frequency

dbSNP / gnomAD

No gnomAD frequency available for this variant. This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: TMC1
Protein: p.Arg74fs
Coding: c.215_219dup
MANE Select: NM_138691
dbSNP: rs730880359
Type: Duplication
Location: chr9:72694692 (GRCh38)
Gene constraint: LOEUF 0.914 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.96 · 1 PDB
Residue 74: the 'disordered' region

Full TMC1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Rare genetic deafness — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TMC1 p.Arg74_Leu75insArg Uncertain significance ★ same residue
TMC1 c.1763+3A>G Pathogenic/Likely pathogenic ★★ same condition
TMC1 c.741+1G>A Pathogenic/Likely pathogenic ★★ same condition
TMC1 p.Arg389Ter Pathogenic ★★ same condition
TMC1 p.Met413fs Pathogenic ★★ same condition
TMC1 p.Pro225Leu Likely pathogenic ★★ same condition
TMC1 p.Ser647Pro Pathogenic/Likely pathogenic ★★ same condition
TMC1 p.Trp559Ter Pathogenic/Likely 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/tmc1-p-arg74fs (accessed [today's date]).

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