Is JPH2 p.Glu559= (c.1677G>A) pathogenic?

JPH2 p.Glu559= (c.1677G>A) is classified Likely benign in JPH2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-01-19). Ultra-rare (popmax 0.0496%, sas); Associated with hypertrophic cardiomyopathy.

What condition is associated with JPH2 p.Glu559= (c.1677G>A)?

JPH2 p.Glu559= (c.1677G>A) is associated with hypertrophic cardiomyopathy (ClinVar).

How common is JPH2 p.Glu559= (c.1677G>A) in the general population?

JPH2 p.Glu559= (c.1677G>A) is ultra-rare (popmax 0.0496%, sas) (gnomAD).

JPH2 p.Glu559=

c.1677G>A · rs758352249 · VCV2447032

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0496%, sas)

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 3.3	GERP 1.3, phastCons 1
Overall
CADD	12.75	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0496% South Asian · 44/88,696 alleles

Filtering AF 0.0379% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0339%

Overall 0.00336% 53/1,579,350 alleles · ultra-rare exomes 51/1,427,212 · genomes 2/152,138 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0496%	2,016
European (non-Finnish)	0.000769%	130,100

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.Glu559=
Coding: c.1677G>A
MANE Select: NM_020433
dbSNP: rs758352249
Type: single nucleotide variant
Location: chr20:44115998 (GRCh38)
Gene constraint: LOEUF 1.051 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.09 · 2 PDB
Residue 559: 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.Glu559Ala Uncertain significance ★ ⚠ same residue
JPH2 p.Glu559Asp Uncertain significance ★ ⚠ 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

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-glu559 (accessed [today's date]).

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