Is TMC1 p.Arg34Ter (c.100C>T) pathogenic?

TMC1 p.Arg34Ter (c.100C>T) is classified Pathogenic in TMC1 (ClinVar, Multiple submitters, 18 submitters; last evaluated 2026-01-22). Ultra-rare (popmax 0.0198%, sas); Associated with TMC1-related disorder.

What condition is associated with TMC1 p.Arg34Ter (c.100C>T)?

TMC1 p.Arg34Ter (c.100C>T) is associated with TMC1-related disorder, autosomal recessive nonsyndromic hearing loss 7, autosomal dominant nonsyndromic hearing loss 36 (ClinVar).

How common is TMC1 p.Arg34Ter (c.100C>T) in the general population?

TMC1 p.Arg34Ter (c.100C>T) is ultra-rare (popmax 0.0198%, sas) (gnomAD).

TMC1 p.Arg34Ter

c.100C>T · rs121908073 · VCV4103

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 18 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0198%, sas)

Conditions

TMC1-related disorder

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 7 of 24
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.6	GERP -3.6, phastCons 0.7
Overall
CADD	35.0	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 0.0198% South Asian · 18/90,990 alleles

Filtering AF 0.0127% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0106%

Overall 0.00217% 35/1,612,698 alleles · ultra-rare exomes 33/1,460,652 · genomes 2/152,046 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0198%	5,055
Middle Eastern	0.0165%	6,052
Remaining individualsnot grpmax-eligible	0.0032%	31,218
East Asian	0.00224%	44,666
European (non-Finnish)	0.0011%	90,718

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.Arg34Ter
Coding: c.100C>T
MANE Select: NM_138691
dbSNP: rs121908073
Type: single nucleotide variant
Location: chr9:72694578 (GRCh38)
Gene constraint: LOEUF 0.914 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.96 · 1 PDB
Residue 34: the 'disordered' region

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

Disease context

TMC1-related disorder

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

Similar variants

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
TMC1 p.Arg389Gln 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-arg34ter (accessed [today's date]).

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