Is JPH2 p.Pro599Arg (c.1796C>G) pathogenic?

JPH2 p.Pro599Arg (c.1796C>G) is classified Uncertain significance in JPH2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-04-01). AlphaMissense: likely benign (0.0711); Ultra-rare (popmax 0.0235%, sas); Associated with Cardiovascular phenotype.

What condition is associated with JPH2 p.Pro599Arg (c.1796C>G)?

JPH2 p.Pro599Arg (c.1796C>G) is associated with Cardiovascular phenotype (ClinVar).

How common is JPH2 p.Pro599Arg (c.1796C>G) in the general population?

JPH2 p.Pro599Arg (c.1796C>G) is ultra-rare (popmax 0.0235%, sas) (gnomAD).

What do computational predictors say about JPH2 p.Pro599Arg (c.1796C>G)?

AlphaMissense predicts likely benign (score 0.0711) — an in-silico prediction, not a clinical call.

JPH2 p.Pro599Arg

c.1796C>G · rs770986432 · VCV1780264

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0711 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0235%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.0711	likely benign
REVEL	0.126	moderately benign-leaning
SaProt	LLR -7.61	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 8.9	GERP 0.71, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 72 kb · p 0.022 · regional, not allelic
Overall
CADD	20.7	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 0.0235% South Asian · 21/89,478 alleles

Filtering AF 0.0156% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0131%

Overall 0.00145% 23/1,582,102 alleles · ultra-rare exomes 19/1,429,820 · genomes 4/152,282 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0235%	4,261
Middle Eastern	0.0175%	5,710
Remaining individualsnot grpmax-eligible	0.00163%	61,412

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.Pro599Arg
Coding: c.1796C>G
MANE Select: NM_020433
dbSNP: rs770986432
Type: single nucleotide variant
Location: chr20:44115879 (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

Similar variants

JPH2 p.Pro599Ala 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 c.-4T>A Uncertain significance ★★ same condition
JPH2 p.Ala214Glu Uncertain significance ★★ ⚠ same condition
JPH2 p.Ala23Thr Uncertain significance ★★ ⚠ same condition
JPH2 p.Ala23Val 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-pro599arg (accessed [today's date]).

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