Is TRPM4 p.Ser206= (c.618G>A) pathogenic?

TRPM4 p.Ser206= (c.618G>A) is classified Benign/Likely benign in TRPM4 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-01-28). Low-frequency (popmax 2.05%, sas); Associated with Cardiovascular phenotype.

What condition is associated with TRPM4 p.Ser206= (c.618G>A)?

TRPM4 p.Ser206= (c.618G>A) is associated with Cardiovascular phenotype, progressive familial heart block type IB (ClinVar).

How common is TRPM4 p.Ser206= (c.618G>A) in the general population?

TRPM4 p.Ser206= (c.618G>A) is low-frequency (popmax 2.05%, sas) (gnomAD).

TRPM4 p.Ser206=

c.618G>A · rs142788545 · VCV264212

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

gnomAD v4.1

Rare

low-frequency (popmax 2.05%, sas)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -20
Overall
CADD	0.053	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 2.05% South Asian · 1,870/91,084 alleles

Filtering AF 1.98% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.94%

Overall 0.259% 4,176/1,613,880 alleles · low-frequency exomes 3,495/1,461,636 · genomes 681/152,244 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	2.05%	49
African / African-American	1.23%	81
Middle Eastern	1.15%	87
Remaining individualsnot grpmax-eligible	0.304%	329
Admixed American	0.147%	682
European (non-Finnish)	0.0855%	1,169
Ashkenazi Jewishnot grpmax-eligible	0.027%	3,701
East Asian	0.0156%	6,411
Finnishnot grpmax-eligible	0.0141%	7,088

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.Ser206=
Coding: c.618G>A
MANE Select: NM_017636
dbSNP: rs142788545
Type: single nucleotide variant
Location: chr19:49168558 (GRCh38)
Gene constraint: LOEUF 1.084 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.51 · 42 PDB
Residue 206: a β-strand

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.Ser206Leu 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-ser206 (accessed [today's date]).

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