Is TRPM4 p.Pro700Ser (c.2098C>T) pathogenic?

TRPM4 p.Pro700Ser (c.2098C>T) is classified Uncertain significance in TRPM4 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-11-23). AlphaMissense: likely pathogenic (0.6988); Very rare (popmax 0.00167%, amr); Associated with Cardiovascular phenotype.

What condition is associated with TRPM4 p.Pro700Ser (c.2098C>T)?

TRPM4 p.Pro700Ser (c.2098C>T) is associated with Cardiovascular phenotype (ClinVar).

How common is TRPM4 p.Pro700Ser (c.2098C>T) in the general population?

TRPM4 p.Pro700Ser (c.2098C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about TRPM4 p.Pro700Ser (c.2098C>T)?

AlphaMissense predicts likely pathogenic (score 0.6988) — an in-silico prediction, not a clinical call.

TRPM4 p.Pro700Ser

c.2098C>T · rs555253063 · VCV1785825

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6988 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.6988	likely pathogenic
REVEL	0.631	indeterminate
SaProt	LLR -10.61	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 43 kb · p 0.93 · regional, not allelic
Overall
CADD	24.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/59,982 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.00031% 5/1,613,834 alleles · very rare exomes 3/1,461,864 · genomes 2/151,970 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	59,982
European (non-Finnish)	0.000339%	294,999

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.Pro700Ser
Coding: c.2098C>T
MANE Select: NM_017636
dbSNP: rs555253063
Type: single nucleotide variant
Location: chr19:49190286 (GRCh38)
Gene constraint: LOEUF 1.084 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.51 · 42 PDB
Residue 700: an α-helix

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.Pro700Thr 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
TRPM4 c.2953+1G>A Uncertain significance ★★ same condition
TRPM4 c.2953+5G>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-pro700ser (accessed [today's date]).

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