Is JPH2 p.Ser590= (c.1770C>T) pathogenic?

JPH2 p.Ser590= (c.1770C>T) is classified Likely benign in JPH2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-11-23). Very rare (popmax 0.00356%, amr); Associated with Cardiovascular phenotype.

What condition is associated with JPH2 p.Ser590= (c.1770C>T)?

JPH2 p.Ser590= (c.1770C>T) is associated with Cardiovascular phenotype, hypertrophic cardiomyopathy (ClinVar).

How common is JPH2 p.Ser590= (c.1770C>T) in the general population?

JPH2 p.Ser590= (c.1770C>T) is very rare (popmax 0.00356%, amr) (gnomAD).

JPH2 p.Ser590=

c.1770C>T · rs755757325 · VCV1142571

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00356%, amr)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.58	GERP -3
Overall
CADD	6.238	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00356% Admixed American · 2/56,162 alleles

Filtering AF 0.000591% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000263%

Overall 0.00089% 14/1,573,738 alleles · very rare exomes 10/1,421,670 · genomes 4/152,068 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00356%	28,081
South Asian	0.00225%	44,409
Remaining individualsnot grpmax-eligible	0.00164%	61,128
European (non-Finnish)	0.000772%	129,592

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.Ser590=
Coding: c.1770C>T
MANE Select: NM_020433
dbSNP: rs755757325
Type: single nucleotide variant
Location: chr20:44115905 (GRCh38)
Gene constraint: LOEUF 1.051 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.09 · 2 PDB
Residue 590: 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-ser590 (accessed [today's date]).

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