Is TRPM4 p.Val736= (c.2208C>G) pathogenic?

TRPM4 p.Val736= (c.2208C>G) is classified Uncertain significance in TRPM4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-29). Very rare (popmax 0.0011%, sas); Associated with progressive familial heart block type IB.

What condition is associated with TRPM4 p.Val736= (c.2208C>G)?

TRPM4 p.Val736= (c.2208C>G) is associated with progressive familial heart block type IB (ClinVar).

How common is TRPM4 p.Val736= (c.2208C>G) in the general population?

TRPM4 p.Val736= (c.2208C>G) is very rare (popmax 0.0011%, sas) (gnomAD).

TRPM4 p.Val736=

Q: How is Hereditary progressive cardiac conduction defect inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

c.2208C>G · rs139307985 · VCV2979544

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Conditions

progressive familial heart block type IB

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.20	donor loss · deltas
Pangolin	Δ0.22	loss · gain 0.01 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP -4.8
Overall
CADD	0.118	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,074 alleles

Overall 0.000186% 3/1,614,030 alleles · very rare exomes 3/1,461,798 · genomes 0/152,232 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,500
South Asiangrpmax	0.0011%	91,074
European (non-Finnish)	8.47e-05%	1,179,965

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: TRPM4
Protein: p.Val736=
Coding: c.2208C>G
MANE Select: NM_017636
dbSNP: rs139307985
Type: single nucleotide variant
Location: chr19:49190771 (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

progressive familial heart block type IB — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Hereditary progressive cardiac conduction defect (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult

Similar variants

TRPM4 p.Val736Phe Uncertain significance ★ ⚠ same residue
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

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-val736 (accessed [today's date]).

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