Is JPH2 p.Arg522Trp (c.1564C>T) pathogenic?

JPH2 p.Arg522Trp (c.1564C>T) is classified Uncertain significance in JPH2 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2025-10-08). AlphaMissense: likely benign (0.2108); Ultra-rare (popmax 0.0217%, mid); Associated with Cardiovascular phenotype.

What condition is associated with JPH2 p.Arg522Trp (c.1564C>T)?

JPH2 p.Arg522Trp (c.1564C>T) is associated with Cardiovascular phenotype, hypertrophic cardiomyopathy (ClinVar).

How common is JPH2 p.Arg522Trp (c.1564C>T) in the general population?

JPH2 p.Arg522Trp (c.1564C>T) is ultra-rare (popmax 0.0217%, mid) (gnomAD).

What do computational predictors say about JPH2 p.Arg522Trp (c.1564C>T)?

AlphaMissense predicts likely benign (score 0.2108) — an in-silico prediction, not a clinical call.

JPH2 p.Arg522Trp

c.1564C>T · rs770850932 · VCV222659

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.2108 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0217%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.2108	likely benign
REVEL	0.11	moderately benign-leaning
SaProt	LLR -9.88	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 3.3	GERP 0.65, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 72 kb · p 0.022 · regional, not allelic
Overall
CADD	23.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0217% Middle Eastern · 1/4,598 alleles

Filtering AF 0.00116% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000942%

Overall 0.00142% 21/1,479,284 alleles · ultra-rare exomes 18/1,327,234 · genomes 3/152,050 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0217%	4,598
European (non-Finnish)	0.00178%	56,336

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.Arg522Trp
Coding: c.1564C>T
MANE Select: NM_020433
dbSNP: rs770850932
Type: single nucleotide variant
Location: chr20:44116111 (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

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hypertrophic cardiomyopathy

Similar variants

JPH2 p.Arg522= Benign/Likely benign ★★ same residue
JPH2 p.Arg522Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
JPH2 p.Thr161Lys Pathogenic/Likely pathogenic ★★ same condition
JPH2 c.-4T>A 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.Ala23Thr 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-arg522trp (accessed [today's date]).

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