Is JPH2 p.Pro619Ala (c.1855C>G) pathogenic?

JPH2 p.Pro619Ala (c.1855C>G) is classified Uncertain significance in JPH2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-25). AlphaMissense: likely benign (0.0492); Very rare (popmax 0.00267%, afr); Associated with Cardiovascular phenotype.

What condition is associated with JPH2 p.Pro619Ala (c.1855C>G)?

JPH2 p.Pro619Ala (c.1855C>G) is associated with Cardiovascular phenotype (ClinVar).

How common is JPH2 p.Pro619Ala (c.1855C>G) in the general population?

JPH2 p.Pro619Ala (c.1855C>G) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about JPH2 p.Pro619Ala (c.1855C>G)?

AlphaMissense predicts likely benign (score 0.0492) — an in-silico prediction, not a clinical call.

JPH2 p.Pro619Ala

c.1855C>G · rs749196483 · VCV3227382

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0492 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.0492	likely benign
REVEL	0.103	moderately benign-leaning
SaProt	LLR -7.17	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 4.6	GERP 0.7, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 72 kb · p 0.022 · regional, not allelic
Overall
CADD	15.5	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 0.00267% African / African-American · 2/74,864 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00026%

Overall 0.000749% 12/1,602,580 alleles · very rare exomes 10/1,450,388 · genomes 2/152,192 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,432
Remaining individualsnot grpmax-eligible	0.00161%	62,244
European (non-Finnish)	0.000764%	130,928

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.Pro619Ala
Coding: c.1855C>G
MANE Select: NM_020433
dbSNP: rs749196483
Type: single nucleotide variant
Location: chr20:44115820 (GRCh38)
Gene constraint: LOEUF 1.051 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.09 · 2 PDB
Residue 619: 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.Pro619= Likely benign ★ 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
JPH2 p.Ala394Thr Uncertain significance ★★ ⚠ same condition
JPH2 p.Ala401Val Uncertain significance ★★ ⚠ same condition
JPH2 p.Ala419Ser 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-pro619ala (accessed [today's date]).

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