Is TMC1 p.Arg752Ter (c.2254C>T) pathogenic?

TMC1 p.Arg752Ter (c.2254C>T) is classified Uncertain significance in TMC1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-11-23). Very rare (popmax 0.00984%, nfe).

How common is TMC1 p.Arg752Ter (c.2254C>T) in the general population?

TMC1 p.Arg752Ter (c.2254C>T) is very rare (popmax 0.00984%, nfe) (gnomAD).

TMC1 p.Arg752Ter

c.2254C>T · rs149506642 · VCV1049283

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00984%, nfe)

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	escapes	premature termination codon within the last 50 nt of the penultimate exon (23 of 24, 6 nt from its 3' end) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 1.4	GERP 0.97, phastCons 0.78
Overall
CADD	38.0	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 0.00984% European (non-Finnish) · 116/1,179,410 alleles

Filtering AF 0.00834% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00777%

Overall 0.00819% 132/1,612,188 alleles · very rare exomes 118/1,461,130 · genomes 14/151,058 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0128%	7,807
European (non-Finnish)grpmax	0.00984%	10,167
African / African-American	0.00537%	18,632
East Asian	0.00446%	22,427
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,596
South Asian	0.0011%	90,928

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.Arg752Ter
Coding: c.2254C>T
MANE Select: NM_138691
dbSNP: rs149506642
Type: single nucleotide variant
Location: chr9:72830676 (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

Similar variants

TMC1 c.1405-2A>T Likely pathogenic ★★ same type
TMC1 c.1763+3A>G Pathogenic/Likely pathogenic ★★ same type
TMC1 c.236+1G>A Pathogenic ★★ same type
TMC1 c.236+1G>T Pathogenic ★★ same type
TMC1 c.64+2T>A Pathogenic/Likely pathogenic ★★ same type
TMC1 c.741+1G>A Pathogenic/Likely pathogenic ★★ same type
TMC1 c.884+1G>A Pathogenic ★★ same type
TMC1 p.Arg264Ter Pathogenic ★★ same type

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-arg752ter (accessed [today's date]).

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