Is JPH2 p.Arg231Gln (c.692G>A) pathogenic?

JPH2 p.Arg231Gln (c.692G>A) is classified Conflicting classifications of pathogenicity in JPH2 (ClinVar, Conflicting submitters, 9 submitters; last evaluated 2026-07-29). AlphaMissense: likely benign (0.1165); Ultra-rare (popmax 0.0588%, nfe); Associated with cardiomyopathy, dilated, 2E.

What condition is associated with JPH2 p.Arg231Gln (c.692G>A)?

JPH2 p.Arg231Gln (c.692G>A) is associated with cardiomyopathy, dilated, 2E, hypertrophic cardiomyopathy, hypertrophic cardiomyopathy 17 (ClinVar).

How common is JPH2 p.Arg231Gln (c.692G>A) in the general population?

JPH2 p.Arg231Gln (c.692G>A) is ultra-rare (popmax 0.0588%, nfe) (gnomAD).

How is Familial isolated dilated cardiomyopathy inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about JPH2 p.Arg231Gln (c.692G>A)?

AlphaMissense predicts likely benign (score 0.1165) — an in-silico prediction, not a clinical call.

JPH2 p.Arg231Gln

c.692G>A · rs761591158 · VCV225099

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 9 submitters

AlphaMissense

likely benign

0.1165 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0588%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

cardiomyopathy, dilated, 2E

Computational evidence

Protein change
AlphaMissense	0.1165	likely benign
REVEL	0.183	benign-leaning
SaProt	LLR -9.57	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 4.4	GERP -1.9, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 72 kb · p 0.022 · regional, not allelic
Overall
CADD	21.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0588% European (non-Finnish) · 672/1,143,522 alleles

Filtering AF 0.0551% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0536%

Overall 0.0475% 727/1,530,048 alleles · ultra-rare exomes 670/1,378,216 · genomes 57/151,832 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0588%	1,702
Remaining individualsnot grpmax-eligible	0.0504%	1,986
Admixed American	0.0355%	2,813
African / African-American	0.00825%	12,121
South Asian	0.00119%	83,784

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.Arg231Gln
Coding: c.692G>A
MANE Select: NM_020433
dbSNP: rs761591158
Type: single nucleotide variant
Location: chr20:44160095 (GRCh38)
Gene constraint: LOEUF 1.051 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.09 · 2 PDB

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

Disease context

cardiomyopathy, dilated, 2E — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hypertrophic cardiomyopathy hypertrophic cardiomyopathy 17

For Familial isolated dilated cardiomyopathy (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, Mitochondrial inheritance
Onset: All ages
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

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
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-arg231gln (accessed [today's date]).

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