Is JPH2 p.Pro580= (c.1740C>A) pathogenic?

JPH2 p.Pro580= (c.1740C>A) is classified Likely benign in JPH2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-11-14). Ultra-rare (popmax 0.0172%, mid); Associated with Cardiovascular phenotype.

What condition is associated with JPH2 p.Pro580= (c.1740C>A)?

JPH2 p.Pro580= (c.1740C>A) is associated with Cardiovascular phenotype, hypertrophic cardiomyopathy (ClinVar).

How common is JPH2 p.Pro580= (c.1740C>A) in the general population?

JPH2 p.Pro580= (c.1740C>A) is ultra-rare (popmax 0.0172%, mid) (gnomAD).

JPH2 p.Pro580=

c.1740C>A · rs779868269 · VCV1102993

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0172%, mid)

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 3	GERP 0.32, phastCons 1
Overall
CADD	9.835	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0172% Middle Eastern · 1/5,816 alleles

Filtering AF 0.00628% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00471%

Overall 0.000891% 14/1,570,450 alleles · ultra-rare exomes 13/1,418,272 · genomes 1/152,178 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0172%	5,816
African / African-American	0.0121%	8,260
Admixed American	0.00541%	18,469
Remaining individualsnot grpmax-eligible	0.00164%	61,144

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.Pro580=
Coding: c.1740C>A
MANE Select: NM_020433
dbSNP: rs779868269
Type: single nucleotide variant
Location: chr20:44115935 (GRCh38)
Gene constraint: LOEUF 1.051 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.09 · 2 PDB
Residue 580: 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.Pro580His Uncertain significance ★★ ⚠ same residue
JPH2 p.Pro580Leu Uncertain significance ★ ⚠ 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

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-pro580 (accessed [today's date]).

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