Is TMC1 p.Asp15= (c.45C>T) pathogenic?

TMC1 p.Asp15= (c.45C>T) is classified Benign in TMC1 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-02-04). Common (popmax 73.1%, afr) — too common for a highly-penetrant pathogenic allele; Associated with autosomal recessive nonsyndromic hearing loss 7.

What condition is associated with TMC1 p.Asp15= (c.45C>T)?

TMC1 p.Asp15= (c.45C>T) is associated with autosomal recessive nonsyndromic hearing loss 7, autosomal dominant nonsyndromic hearing loss 36 (ClinVar).

TMC1 p.Asp15=

Q: How common is TMC1 p.Asp15= (c.45C>T) in the general population?

TMC1 p.Asp15= (c.45C>T) is common (popmax 73.1%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.45C>T · rs2589615 · VCV47874

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

gnomAD v4.1

Common

common (popmax 73.1%, afr) — too common for a highly-penetrant pathogenic allele

Conditions

autosomal recessive nonsyndromic hearing loss 7

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 -5	GERP -4
Overall
CADD	5.783	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 73.1% African / African-American · 54,603/74,730 alleles

Filtering AF 72.6% ClinGen BA1/BS1 input FAF95, joint · FAF99 72.3%

Overall 43.5% 698,187/1,603,854 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	73.1%	1
Middle Eastern	49.6%	2
Admixed American	46.7%	2
Ashkenazi Jewishnot grpmax-eligible	45.9%	2
Remaining individualsnot grpmax-eligible	45.1%	2
Amishnot grpmax-eligible	44.7%	2
East Asian	44%	2
Finnishnot grpmax-eligible	43.6%	2
South Asian	43%	2
European (non-Finnish)	41.3%	2

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.Asp15=
Coding: c.45C>T
MANE Select: NM_138691
dbSNP: rs2589615
Type: single nucleotide variant
Location: chr9:72688737 (GRCh38)
Gene constraint: LOEUF 0.914 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.96 · 1 PDB
Residue 15: the 'disordered' region

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

Disease context

autosomal recessive nonsyndromic hearing loss 7 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: autosomal dominant nonsyndromic hearing loss 36

Similar variants

TMC1 p.Asp15Ala Uncertain significance ★ ⚠ same residue
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
TMC1 c.64+2T>A Pathogenic/Likely pathogenic ★★ same condition
TMC1 c.741+1G>A Pathogenic/Likely pathogenic ★★ same condition
TMC1 c.884+1G>A Pathogenic ★★ same condition
TMC1 p.Arg264Ter 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-asp15 (accessed [today's date]).

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