Is JPH2 p.Glu586= (c.1758G>A) pathogenic?

JPH2 p.Glu586= (c.1758G>A) is classified Likely benign in JPH2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-07-16). Ultra-rare (popmax 0.0173%, mid); Associated with hypertrophic cardiomyopathy.

What condition is associated with JPH2 p.Glu586= (c.1758G>A)?

JPH2 p.Glu586= (c.1758G>A) is associated with hypertrophic cardiomyopathy (ClinVar).

How common is JPH2 p.Glu586= (c.1758G>A) in the general population?

JPH2 p.Glu586= (c.1758G>A) is ultra-rare (popmax 0.0173%, mid) (gnomAD).

JPH2 p.Glu586=

c.1758G>A · rs753383507 · VCV520524

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0173%, mid)

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 -0.09	GERP 0.34
Overall
CADD	8.21	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0173% Middle Eastern · 1/5,774 alleles

Filtering AF 0.00346% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0022%

Overall 0.000955% 15/1,571,366 alleles · ultra-rare exomes 13/1,419,222 · genomes 2/152,144 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0173%	5,774
Admixed American	0.00898%	11,134
African / African-American	0.00269%	37,155
Remaining individualsnot grpmax-eligible	0.00164%	61,114
European (non-Finnish)	0.000515%	194,211

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.Glu586=
Coding: c.1758G>A
MANE Select: NM_020433
dbSNP: rs753383507
Type: single nucleotide variant
Location: chr20:44115917 (GRCh38)
Gene constraint: LOEUF 1.051 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.09 · 2 PDB
Residue 586: 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.Glu586Lys Conflicting classifications of pathogenicity ★ ⚠ same residue
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

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-glu586 (accessed [today's date]).

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