Is TMC1 p.Arg389Ter (c.1165C>T) pathogenic?

TMC1 p.Arg389Ter (c.1165C>T) is classified Pathogenic in TMC1 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-08-12). Ultra-rare (popmax 0.0168%, nfe); Associated with Rare genetic deafness.

What condition is associated with TMC1 p.Arg389Ter (c.1165C>T)?

TMC1 p.Arg389Ter (c.1165C>T) is associated with Rare genetic deafness, autosomal recessive nonsyndromic hearing loss 7, autosomal dominant nonsyndromic hearing loss 36 (ClinVar).

How common is TMC1 p.Arg389Ter (c.1165C>T) in the general population?

TMC1 p.Arg389Ter (c.1165C>T) is ultra-rare (popmax 0.0168%, nfe) (gnomAD).

TMC1 p.Arg389Ter

c.1165C>T · rs151001642 · VCV47856

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0168%, nfe)

Conditions

Rare genetic deafness

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 15 of 24
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.009	GERP -1.5, phastCons 0.76
Overall
CADD	36.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0168% European (non-Finnish) · 198/1,179,926 alleles

Filtering AF 0.0149% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0141%

Overall 0.0136% 219/1,613,974 alleles · ultra-rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0224%	4,464
European (non-Finnish)grpmax	0.0168%	5,959
African / African-American	0.00533%	18,755
Admixed American	0.00333%	30,002
East Asian	0.00223%	44,872

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg389Ter
Coding: c.1165C>T
MANE Select: NM_138691
dbSNP: rs151001642
Type: single nucleotide variant
Location: chr9:72789258 (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

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

Also linked: autosomal recessive nonsyndromic hearing loss 7 autosomal dominant nonsyndromic hearing loss 36

Similar variants

TMC1 p.Arg389Gln Pathogenic/Likely 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-arg389ter (accessed [today's date]).

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