Is TMC1 p.Pro421= (c.1263A>G) pathogenic?

TMC1 p.Pro421= (c.1263A>G) is classified Conflicting classifications of pathogenicity in TMC1 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-01-20). Rare (popmax 0.372%, mid); Associated with autosomal recessive nonsyndromic hearing loss 7.

What condition is associated with TMC1 p.Pro421= (c.1263A>G)?

TMC1 p.Pro421= (c.1263A>G) is associated with autosomal recessive nonsyndromic hearing loss 7, autosomal dominant nonsyndromic hearing loss 36 (ClinVar).

How common is TMC1 p.Pro421= (c.1263A>G) in the general population?

TMC1 p.Pro421= (c.1263A>G) is rare (popmax 0.372%, mid) (gnomAD).

TMC1 p.Pro421=

c.1263A>G · rs139985214 · VCV178545

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

rare (popmax 0.372%, mid)

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 1.1	GERP -4.5, phastCons 0.99
Overall
CADD	9.609	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.372% Middle Eastern · 21/5,652 alleles

Filtering AF 0.249% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.209%

Overall 0.0057% 92/1,613,472 alleles · rare exomes 82/1,461,262 · genomes 10/152,210 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.372%	269
Remaining individualsnot grpmax-eligible	0.0112%	8,922
Admixed American	0.00833%	12,000
South Asian	0.00769%	13,008
European (non-Finnish)	0.00441%	22,692

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.Pro421=
Coding: c.1263A>G
MANE Select: NM_138691
dbSNP: rs139985214
Type: single nucleotide variant
Location: chr9:72791924 (GRCh38)
Gene constraint: LOEUF 0.914 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.96 · 1 PDB

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.Pro421Leu Pathogenic ★ 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-pro421 (accessed [today's date]).

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