Is TRPM4 p.Lys712= (c.2136A>G) pathogenic?

TRPM4 p.Lys712= (c.2136A>G) is classified Conflicting classifications of pathogenicity in TRPM4 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2023-05-18). Very rare (popmax 0.00401%, afr); Associated with Cardiovascular phenotype.

What condition is associated with TRPM4 p.Lys712= (c.2136A>G)?

TRPM4 p.Lys712= (c.2136A>G) is associated with Cardiovascular phenotype, progressive familial heart block type IB (ClinVar).

How common is TRPM4 p.Lys712= (c.2136A>G) in the general population?

TRPM4 p.Lys712= (c.2136A>G) is very rare (popmax 0.00401%, afr) (gnomAD).

TRPM4 p.Lys712=

c.2136A>G · rs368500945 · VCV1561640

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00401%, afr)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.29	acceptor gain · deltas
Pangolin	Δ0.27	gain · loss 0.08 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 1.6	phastCons 0.85
Overall
CADD	12.35	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00401% African / African-American · 3/74,902 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.000186% 3/1,613,996 alleles · very rare exomes 1/1,461,874 · genomes 2/152,122 · joint denominator

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.Lys712=
Coding: c.2136A>G
MANE Select: NM_017636
dbSNP: rs368500945
Type: single nucleotide variant
Location: chr19:49190699 (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

Also linked: progressive familial heart block type IB

Similar variants

TRPM4 p.Ile1040Thr Pathogenic/Likely pathogenic ★★ same condition
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.1150+6A>G Uncertain significance ★★ same condition
TRPM4 c.1263+1G>A Uncertain significance ★★ same condition
TRPM4 c.1263+2T>G Uncertain significance ★★ same condition
TRPM4 c.1608+1G>C 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-lys712 (accessed [today's date]).

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