Is JPH2 p.Pro599Ala (c.1795C>G) pathogenic?

JPH2 p.Pro599Ala (c.1795C>G) is classified Uncertain significance in JPH2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-05-30). AlphaMissense: likely benign (0.0536); Very rare (popmax 0.00345%, amr); Associated with Cardiovascular phenotype.

What condition is associated with JPH2 p.Pro599Ala (c.1795C>G)?

JPH2 p.Pro599Ala (c.1795C>G) is associated with Cardiovascular phenotype, hypertrophic cardiomyopathy (ClinVar).

How common is JPH2 p.Pro599Ala (c.1795C>G) in the general population?

JPH2 p.Pro599Ala (c.1795C>G) is very rare (popmax 0.00345%, amr) (gnomAD).

What do computational predictors say about JPH2 p.Pro599Ala (c.1795C>G)?

AlphaMissense predicts likely benign (score 0.0536) — an in-silico prediction, not a clinical call.

JPH2 p.Pro599Ala

c.1795C>G · rs745811880 · VCV2156549

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0536 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00345%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.0536	likely benign
REVEL	0.077	moderately benign-leaning
SaProt	LLR -6.90	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 0.71, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 72 kb · p 0.022 · regional, not allelic
Overall
CADD	17.77	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 0.00345% Admixed American · 2/58,030 alleles

Filtering AF 0.000572% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000214%

Overall 0.000316% 5/1,583,146 alleles · very rare exomes 4/1,430,986 · genomes 1/152,160 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00345%	29,015
European (non-Finnish)	0.000256%	390,276

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.Pro599Ala
Coding: c.1795C>G
MANE Select: NM_020433
dbSNP: rs745811880
Type: single nucleotide variant
Location: chr20:44115880 (GRCh38)
Gene constraint: LOEUF 1.051 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.09 · 2 PDB
Residue 599: 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.Pro599Arg Uncertain significance ★★ ⚠ same residue
JPH2 p.Pro599= Likely benign ★★ same residue
JPH2 p.Pro599Leu Uncertain significance ★ ⚠ same residue
JPH2 p.Pro599Ser Uncertain significance ★ ⚠ 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

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-pro599ala (accessed [today's date]).

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