Is JPH2 p.Arg522= (c.1566G>A) pathogenic?

JPH2 p.Arg522= (c.1566G>A) is classified Benign/Likely benign in JPH2 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-02-02). Ultra-rare (popmax 0.0935%, afr); Associated with hypertrophic cardiomyopathy 17.

What condition is associated with JPH2 p.Arg522= (c.1566G>A)?

JPH2 p.Arg522= (c.1566G>A) is associated with hypertrophic cardiomyopathy 17, hypertrophic cardiomyopathy, cardiomyopathy, dilated, 2E (ClinVar).

How common is JPH2 p.Arg522= (c.1566G>A) in the general population?

JPH2 p.Arg522= (c.1566G>A) is ultra-rare (popmax 0.0935%, afr) (gnomAD).

JPH2 p.Arg522=

c.1566G>A · rs559143345 · VCV380759

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0935%, afr)

Conditions

hypertrophic cardiomyopathy 17

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 -0.57	GERP -1.3, phastCons 0.056
Overall
CADD	3.538	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0935% African / African-American · 64/68,472 alleles

Filtering AF 0.075% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0684%

Overall 0.0048% 71/1,480,468 alleles · ultra-rare exomes 29/1,328,258 · genomes 42/152,210 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0935%	1,070
Remaining individualsnot grpmax-eligible	0.0105%	9,544
European (non-Finnish)	8.87e-05%	1,127,262

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.Arg522=
Coding: c.1566G>A
MANE Select: NM_020433
dbSNP: rs559143345
Type: single nucleotide variant
Location: chr20:44116109 (GRCh38)
Gene constraint: LOEUF 1.051 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.09 · 2 PDB
Residue 522: 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 17 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hypertrophic cardiomyopathy cardiomyopathy, dilated, 2E

Similar variants

JPH2 p.Arg522Trp Uncertain significance ★★ ⚠ same residue
JPH2 p.Arg522Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
JPH2 p.Thr161Lys Pathogenic/Likely pathogenic ★★ same condition
JPH2 c.*15A>T Uncertain significance ★★ 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

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-arg522 (accessed [today's date]).

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