Is TMC1 p.Val6fs (c.15dup) pathogenic?

TMC1 p.Val6fs (c.15dup) is classified Pathogenic in TMC1 (ClinVar, Single submitter, 2 submitters; last evaluated 2024-01-07). Very rare (popmax 0.0011%, sas); Associated with autosomal dominant nonsyndromic hearing loss 36.

What condition is associated with TMC1 p.Val6fs (c.15dup)?

TMC1 p.Val6fs (c.15dup) is associated with autosomal dominant nonsyndromic hearing loss 36, autosomal recessive nonsyndromic hearing loss 7 (ClinVar).

How common is TMC1 p.Val6fs (c.15dup) in the general population?

TMC1 p.Val6fs (c.15dup) is very rare (popmax 0.0011%, sas) (gnomAD).

TMC1 p.Val6fs

c.15dup · rs878853229 · VCV236041

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Conditions

autosomal dominant nonsyndromic hearing loss 36

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 5 of 24
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.17	GERP -1.5, phastCons 0.96

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,042 alleles

Overall 0.000137% 2/1,460,802 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,042
European (non-Finnish)	8.48e-05%	1,179,033

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: TMC1
Protein: p.Val6fs
Coding: c.15dup
MANE Select: NM_138691
dbSNP: rs878853229
Type: Duplication
Location: chr9:72648657 (GRCh38)
Gene constraint: LOEUF 0.914 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.96 · 1 PDB
Residue 6: the 'disordered' region

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

Disease context

autosomal dominant nonsyndromic hearing loss 36 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: autosomal recessive nonsyndromic hearing loss 7

Similar variants

TMC1 c.535+2dup Pathogenic ★ same condition
TMC1 p.Asn407fs Pathogenic ★ same condition
TMC1 p.Tyr323Ter Pathogenic ★ same condition
TMC1 c.884+2dup Conflicting classifications of pathogenicity ★ same condition
TMC1 c.741+2dup Likely pathogenic same condition
TMC1 c.1405-2A>T Likely pathogenic ★★ same condition
TMC1 c.1763+3A>G Pathogenic/Likely pathogenic ★★ same condition
TMC1 c.236+1G>A 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-val6fs (accessed [today's date]).

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