Is JPH2 p.Leu604= (c.1812G>T) pathogenic?

JPH2 p.Leu604= (c.1812G>T) is classified Likely benign in JPH2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-12-01). Very rare (popmax 0.00339%, amr); Associated with hypertrophic cardiomyopathy.

What condition is associated with JPH2 p.Leu604= (c.1812G>T)?

JPH2 p.Leu604= (c.1812G>T) is associated with hypertrophic cardiomyopathy (ClinVar).

How common is JPH2 p.Leu604= (c.1812G>T) in the general population?

JPH2 p.Leu604= (c.1812G>T) is very rare (popmax 0.00339%, amr) (gnomAD).

JPH2 p.Leu604=

c.1812G>T · rs780290036 · VCV1100289

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00339%, amr)

Conditions

hypertrophic cardiomyopathy

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 -1.6	GERP -2.1
Overall
CADD	0.953	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00339% Admixed American · 2/58,924 alleles

Filtering AF 0.00146% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00124%

Overall 0.00183% 29/1,587,410 alleles · very rare exomes 24/1,435,252 · genomes 5/152,158 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00339%	29,462
European (non-Finnish)	0.00213%	46,899
Remaining individualsnot grpmax-eligible	0.00162%	61,594
African / African-American	0.00134%	74,562

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: JPH2
Protein: p.Leu604=
Coding: c.1812G>T
MANE Select: NM_020433
dbSNP: rs780290036
Type: single nucleotide variant
Location: chr20:44115863 (GRCh38)
Gene constraint: LOEUF 1.051 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.09 · 2 PDB
Residue 604: the 'disordered' region; a UniProt-annotated variant site (in cmd2e; uncertain significance)

Full JPH2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hypertrophic cardiomyopathy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

JPH2 p.Thr161Lys Pathogenic/Likely pathogenic ★★ same condition
JPH2 p.Ala181Thr Uncertain significance ★★ ⚠ same condition
JPH2 p.Ala194Ser Uncertain significance ★★ ⚠ same condition
JPH2 p.Ala214Glu Uncertain significance ★★ ⚠ same condition
JPH2 p.Ala394Thr Uncertain significance ★★ ⚠ same condition
JPH2 p.Ala401Val Uncertain significance ★★ ⚠ same condition
JPH2 p.Ala405Thr Uncertain significance ★★ same condition
JPH2 p.Ala419Ser 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/jph2-p-leu604 (accessed [today's date]).

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