Is JPH2 p.Ala488= (c.1464C>G) pathogenic?

JPH2 p.Ala488= (c.1464C>G) is classified Likely benign in JPH2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-07-26). Very rare (popmax 0.00153%, afr); Associated with Cardiovascular phenotype.

What condition is associated with JPH2 p.Ala488= (c.1464C>G)?

JPH2 p.Ala488= (c.1464C>G) is associated with Cardiovascular phenotype, hypertrophic cardiomyopathy (ClinVar).

How common is JPH2 p.Ala488= (c.1464C>G) in the general population?

JPH2 p.Ala488= (c.1464C>G) is very rare (popmax 0.00153%, afr) (gnomAD).

JPH2 p.Ala488=

c.1464C>G · rs1060499997 · VCV2040923

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00153%, afr)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.24	GERP -1.6, phastCons 0.96
Overall
CADD	2.512	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00153% African / African-American · 1/65,552 alleles

Filtering AF 7.4e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 2e-05%

Overall 0.000287% 4/1,393,742 alleles · very rare exomes 4/1,241,606 · genomes 0/152,136 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00153%	65,552
European (non-Finnish)	0.000276%	361,857

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.Ala488=
Coding: c.1464C>G
MANE Select: NM_020433
dbSNP: rs1060499997
Type: single nucleotide variant
Location: chr20:44116211 (GRCh38)
Gene constraint: LOEUF 1.051 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.09 · 2 PDB
Residue 488: 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.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
JPH2 p.Ala394Thr 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-ala488 (accessed [today's date]).

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