Is JPH2 p.Arg300Pro (c.899G>C) pathogenic?

JPH2 p.Arg300Pro (c.899G>C) is classified Uncertain significance in JPH2 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-12-31). AlphaMissense: likely pathogenic (0.9928); Very rare (popmax 8.48e-05%, nfe); Associated with hypertrophic cardiomyopathy.

What condition is associated with JPH2 p.Arg300Pro (c.899G>C)?

JPH2 p.Arg300Pro (c.899G>C) is associated with hypertrophic cardiomyopathy (ClinVar).

How common is JPH2 p.Arg300Pro (c.899G>C) in the general population?

JPH2 p.Arg300Pro (c.899G>C) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about JPH2 p.Arg300Pro (c.899G>C)?

AlphaMissense predicts likely pathogenic (score 0.9928) — an in-silico prediction, not a clinical call.

JPH2 p.Arg300Pro

c.899G>C · rs2072594403 · VCV844303

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9928 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

hypertrophic cardiomyopathy

Computational evidence

Protein change
AlphaMissense	0.9928	likely pathogenic
REVEL	0.522	indeterminate
SaProt	LLR -14.62	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.4	GERP 1.9, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 72 kb · p 0.022 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 8.48e-05% European (non-Finnish) · 1/1,179,812 alleles

Overall 6.2e-05% 1/1,613,284 alleles · very rare exomes 1/1,461,148 · genomes 0/152,136 · joint denominator

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.Arg300Pro
Coding: c.899G>C
MANE Select: NM_020433
dbSNP: rs2072594403
Type: single nucleotide variant
Location: chr20:44159888 (GRCh38)
Gene constraint: LOEUF 1.051 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.09 · 2 PDB
Residue 300: a β-strand

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.Arg300His Uncertain significance ★ ⚠ same residue
JPH2 p.Arg300Leu Uncertain significance ★ ⚠ same residue
JPH2 p.Arg300Cys Likely benign 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

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-arg300pro (accessed [today's date]).

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