Is JPH2 p.Glu657= (c.1971G>A) pathogenic?

JPH2 p.Glu657= (c.1971G>A) is classified Benign/Likely benign in JPH2 (ClinVar, Multiple submitters, 11 submitters; last evaluated 2026-02-02). Rare (popmax 0.405%, sas); Associated with Cardiovascular phenotype.

What condition is associated with JPH2 p.Glu657= (c.1971G>A)?

JPH2 p.Glu657= (c.1971G>A) is associated with Cardiovascular phenotype, hypertrophic cardiomyopathy, hypertrophic cardiomyopathy 17 (ClinVar).

How common is JPH2 p.Glu657= (c.1971G>A) in the general population?

JPH2 p.Glu657= (c.1971G>A) is rare (popmax 0.405%, sas) (gnomAD).

JPH2 p.Glu657=

c.1971G>A · rs142333841 · VCV137610

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 11 submitters

gnomAD v4.1

Rare

rare (popmax 0.405%, sas)

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 0.58	GERP -1.7, phastCons 1
Overall
CADD	7.359	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.405% South Asian · 369/91,048 alleles

Filtering AF 0.371% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.358%

Overall 0.172% 2,773/1,613,416 alleles · rare exomes 2,612/1,461,046 · genomes 161/152,370 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.405%	247
European (non-Finnish)	0.189%	530
Remaining individualsnot grpmax-eligible	0.17%	589
Amishnot grpmax-eligible	0.11%	912
Admixed American	0.06%	1,668
Middle Eastern	0.054%	1,852
African / African-American	0.036%	2,779
Finnishnot grpmax-eligible	0.00626%	15,975
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,602

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.Glu657=
Coding: c.1971G>A
MANE Select: NM_020433
dbSNP: rs142333841
Type: single nucleotide variant
Location: chr20:44115704 (GRCh38)
Gene constraint: LOEUF 1.051 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.09 · 2 PDB
Residue 657: 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 hypertrophic cardiomyopathy 17

Similar variants

JPH2 p.Thr161Lys Pathogenic/Likely pathogenic ★★ same condition
JPH2 c.-4T>A Uncertain significance ★★ same condition
JPH2 c.*15A>T 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-glu657 (accessed [today's date]).

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