Is JPH2 p.Ala460Val (c.1379C>T) pathogenic?

JPH2 p.Ala460Val (c.1379C>T) is classified Uncertain significance in JPH2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-10-05). AlphaMissense: likely benign (0.0917); Very rare (popmax 0.00493%, eas); Associated with Cardiovascular phenotype.

What condition is associated with JPH2 p.Ala460Val (c.1379C>T)?

JPH2 p.Ala460Val (c.1379C>T) is associated with Cardiovascular phenotype, hypertrophic cardiomyopathy (ClinVar).

How common is JPH2 p.Ala460Val (c.1379C>T) in the general population?

JPH2 p.Ala460Val (c.1379C>T) is very rare (popmax 0.00493%, eas) (gnomAD).

What do computational predictors say about JPH2 p.Ala460Val (c.1379C>T)?

AlphaMissense predicts likely benign (score 0.0917) — an in-silico prediction, not a clinical call.

JPH2 p.Ala460Val

c.1379C>T · rs1158370131 · VCV2557373

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0917 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00493%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.0917	likely benign
REVEL	0.038	moderately benign-leaning
SaProt	LLR -7.74	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 5.9	GERP -0.15, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 72 kb · p 0.022 · regional, not allelic
Overall
CADD	13.88	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 0.00493% East Asian · 2/40,578 alleles

Filtering AF 0.000817% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000306%

Overall 0.00039% 6/1,539,114 alleles · very rare exomes 3/1,386,978 · genomes 3/152,136 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00493%	20,289
Admixed American	0.00197%	50,688
European (non-Finnish)	0.000262%	381,647

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.Ala460Val
Coding: c.1379C>T
MANE Select: NM_020433
dbSNP: rs1158370131
Type: single nucleotide variant
Location: chr20:44116296 (GRCh38)
Gene constraint: LOEUF 1.051 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.09 · 2 PDB
Residue 460: 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.Ala460= Conflicting classifications of pathogenicity ★ 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
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-ala460val (accessed [today's date]).

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