Is TRPM4 p.Phe533= (c.1599C>T) pathogenic?

TRPM4 p.Phe533= (c.1599C>T) is classified Uncertain significance in TRPM4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-06). Very rare (popmax 0.00449%, eas); Associated with progressive familial heart block type IB.

What condition is associated with TRPM4 p.Phe533= (c.1599C>T)?

TRPM4 p.Phe533= (c.1599C>T) is associated with progressive familial heart block type IB (ClinVar).

How common is TRPM4 p.Phe533= (c.1599C>T) in the general population?

TRPM4 p.Phe533= (c.1599C>T) is very rare (popmax 0.00449%, eas) (gnomAD).

TRPM4 p.Phe533=

Q: How is Hereditary progressive cardiac conduction defect inherited?

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

c.1599C>T · rs1131691388 · VCV3227000

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00449%, eas)

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	Δ0.21	donor loss · deltas
Pangolin	Δ0.25	loss · gain 0.10 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 1.6	phastCons 0.008
Overall
CADD	10.63	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00449% East Asian · 2/44,562 alleles

Filtering AF 0.000744% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000278%

Overall 0.000251% 4/1,592,798 alleles · very rare exomes 4/1,440,524 · genomes 0/152,274 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00449%	22,281
South Asian	0.00227%	44,083

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.Phe533=
Coding: c.1599C>T
MANE Select: NM_017636
dbSNP: rs1131691388
Type: single nucleotide variant
Location: chr19:49182913 (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.Phe533Leu 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-phe533 (accessed [today's date]).

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