Is TRPM4 p.Arg755Cys (c.2263C>T) pathogenic?

TRPM4 p.Arg755Cys (c.2263C>T) is classified Likely benign in TRPM4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-06). AlphaMissense: likely benign (0.1048); Ultra-rare (popmax 0.0271%, sas); Associated with Cardiovascular phenotype.

What condition is associated with TRPM4 p.Arg755Cys (c.2263C>T)?

TRPM4 p.Arg755Cys (c.2263C>T) is associated with Cardiovascular phenotype (ClinVar).

How common is TRPM4 p.Arg755Cys (c.2263C>T) in the general population?

TRPM4 p.Arg755Cys (c.2263C>T) is ultra-rare (popmax 0.0271%, sas) (gnomAD).

What do computational predictors say about TRPM4 p.Arg755Cys (c.2263C>T)?

AlphaMissense predicts likely benign (score 0.1048) — an in-silico prediction, not a clinical call.

TRPM4 p.Arg755Cys

c.2263C>T · rs766805975 · VCV1788664

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1048 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0271%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.1048	likely benign
REVEL	0.049	moderately benign-leaning
SaProt	LLR -6.78	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -3.2
Regional constraint	o/e 1.00	unconstrained · MANE · 43 kb · p 0.93 · regional, not allelic
Overall
CADD	15.53	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0271% South Asian · 23/84,878 alleles

Filtering AF 0.0185% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0156%

Overall 0.0018% 28/1,555,508 alleles · ultra-rare exomes 26/1,403,372 · genomes 2/152,136 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0271%	3,690
East Asian	0.00238%	41,934
Remaining individualsnot grpmax-eligible	0.00165%	60,428
European (non-Finnish)	0.00026%	384,638

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: TRPM4
Protein: p.Arg755Cys
Coding: c.2263C>T
MANE Select: NM_017636
dbSNP: rs766805975
Type: single nucleotide variant
Location: chr19:49196492 (GRCh38)
Gene constraint: LOEUF 1.084 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.51 · 42 PDB

Full TRPM4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TRPM4 p.Arg755Ser Uncertain significance ★★ ⚠ same residue
TRPM4 p.Arg755His Conflicting classifications of pathogenicity ★ ⚠ same residue
TRPM4 p.Arg755= Likely benign ★ same residue
TRPM4 p.Ile376Thr Pathogenic/Likely pathogenic ★★ ⚠ same condition
TRPM4 c.1050+1G>A Uncertain significance ★★ same condition
TRPM4 c.1150+5A>T Uncertain significance ★★ same condition
TRPM4 c.2019+5G>A Uncertain significance ★★ same condition
TRPM4 c.2645+1G>A Uncertain significance ★★ 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/trpm4-p-arg755cys (accessed [today's date]).

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