Is JPH2 p.Ile379Val (c.1135A>G) pathogenic?

JPH2 p.Ile379Val (c.1135A>G) is classified Uncertain significance in JPH2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-04). AlphaMissense: likely benign (0.1192); Ultra-rare (popmax 0.0379%, eas); Associated with hypertrophic cardiomyopathy.

What condition is associated with JPH2 p.Ile379Val (c.1135A>G)?

JPH2 p.Ile379Val (c.1135A>G) is associated with hypertrophic cardiomyopathy (ClinVar).

How common is JPH2 p.Ile379Val (c.1135A>G) in the general population?

JPH2 p.Ile379Val (c.1135A>G) is ultra-rare (popmax 0.0379%, eas) (gnomAD).

What do computational predictors say about JPH2 p.Ile379Val (c.1135A>G)?

AlphaMissense predicts likely benign (score 0.1192) — an in-silico prediction, not a clinical call.

JPH2 p.Ile379Val

c.1135A>G · VCV3698386

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1192 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0379%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hypertrophic cardiomyopathy

Computational evidence

Protein change
AlphaMissense	0.1192	likely benign
REVEL	0.078	moderately benign-leaning
SaProt	LLR -8.72	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 7.8	GERP 1.9, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 72 kb · p 0.022 · regional, not allelic
Overall
CADD	20.7	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 0.0379% East Asian · 17/44,876 alleles

Filtering AF 0.0241% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0197%

Overall 0.00112% 18/1,608,536 alleles · ultra-rare exomes 14/1,456,172 · genomes 4/152,364 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0379%	2,640
African / African-American	0.00133%	75,058

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.Ile379Val
Coding: c.1135A>G
MANE Select: NM_020433
Type: single nucleotide variant
Location: chr20:44159652 (GRCh38)
Gene constraint: LOEUF 1.051 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.09 · 2 PDB
Residue 379: an α-helix

Full JPH2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hypertrophic cardiomyopathy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

JPH2 p.Ile379= Benign/Likely benign ★★ same residue
JPH2 p.Ile379Thr Uncertain significance ★ same residue
JPH2 p.Thr161Lys Pathogenic/Likely pathogenic ★★ 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.Ala394Thr Uncertain significance ★★ ⚠ same condition
JPH2 p.Ala401Val 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-ile379val (accessed [today's date]).

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