Is JPH2 p.Pro480Ser (c.1438C>T) pathogenic?

JPH2 p.Pro480Ser (c.1438C>T) is classified Uncertain significance in JPH2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-01-29). AlphaMissense: likely benign (0.075); Very rare (popmax 0.000179%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with JPH2 p.Pro480Ser (c.1438C>T)?

JPH2 p.Pro480Ser (c.1438C>T) is associated with Cardiovascular phenotype (ClinVar).

How common is JPH2 p.Pro480Ser (c.1438C>T) in the general population?

JPH2 p.Pro480Ser (c.1438C>T) is very rare (popmax 0.000179%, nfe) (gnomAD).

What do computational predictors say about JPH2 p.Pro480Ser (c.1438C>T)?

AlphaMissense predicts likely benign (score 0.075) — an in-silico prediction, not a clinical call.

JPH2 p.Pro480Ser

c.1438C>T · rs2515718419 · VCV2451750

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.075 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000179%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.075	likely benign
REVEL	0.077	moderately benign-leaning
SaProt	LLR -5.75	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 11	GERP 0.78, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 72 kb · p 0.022 · regional, not allelic
Overall
CADD	18.58	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 0.000179% European (non-Finnish) · 2/1,114,392 alleles

Filtering AF 3e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,459,014 alleles · very rare exomes 2/1,306,860 · genomes 0/152,154 · 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.Pro480Ser
Coding: c.1438C>T
MANE Select: NM_020433
dbSNP: rs2515718419
Type: single nucleotide variant
Location: chr20:44116237 (GRCh38)
Gene constraint: LOEUF 1.051 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.09 · 2 PDB
Residue 480: 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.Pro480= 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-pro480ser (accessed [today's date]).

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