Is TRPM4 p.Cys20Ser (c.58T>A) pathogenic?

TRPM4 p.Cys20Ser (c.58T>A) is classified Uncertain significance in TRPM4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2016-02-17). AlphaMissense: likely pathogenic (0.9609); Very rare (popmax 0.00892%, eas); Associated with progressive familial heart block type IB.

What condition is associated with TRPM4 p.Cys20Ser (c.58T>A)?

TRPM4 p.Cys20Ser (c.58T>A) is associated with progressive familial heart block type IB (ClinVar).

How common is TRPM4 p.Cys20Ser (c.58T>A) in the general population?

TRPM4 p.Cys20Ser (c.58T>A) is very rare (popmax 0.00892%, eas) (gnomAD).

What do computational predictors say about TRPM4 p.Cys20Ser (c.58T>A)?

AlphaMissense predicts likely pathogenic (score 0.9609) — an in-silico prediction, not a clinical call.

TRPM4 p.Cys20Ser

Q: How is Hereditary progressive cardiac conduction defect inherited?

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

c.58T>A · rs864622643 · VCV220734

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9609 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00892%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

progressive familial heart block type IB

Computational evidence

Protein change
AlphaMissense	0.9609	likely pathogenic · top 4% in TRPM4
REVEL	0.893	moderately pathogenic-leaning
SaProt	LLR -13.10	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 10 kb · p 0.94 · regional, not allelic
Overall
CADD	26.0	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 0.00892% East Asian · 4/44,828 alleles

Filtering AF 0.00298% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0018%

Overall 0.000248% 4/1,613,808 alleles · very rare exomes 3/1,461,810 · genomes 1/151,998 · 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.Cys20Ser
Coding: c.58T>A
MANE Select: NM_017636
dbSNP: rs864622643
Type: single nucleotide variant
Location: chr19:49158225 (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.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-cys20ser (accessed [today's date]).

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