Is JPH2 p.Pro554= (c.1662G>A) pathogenic?

JPH2 p.Pro554= (c.1662G>A) is classified Likely benign in JPH2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-02-05). Ultra-rare (popmax 0.0473%, sas); Associated with Cardiovascular phenotype.

What condition is associated with JPH2 p.Pro554= (c.1662G>A)?

JPH2 p.Pro554= (c.1662G>A) is associated with Cardiovascular phenotype, hypertrophic cardiomyopathy (ClinVar).

How common is JPH2 p.Pro554= (c.1662G>A) in the general population?

JPH2 p.Pro554= (c.1662G>A) is ultra-rare (popmax 0.0473%, sas) (gnomAD).

JPH2 p.Pro554=

c.1662G>A · rs748323930 · VCV381976

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0473%, 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 -2.7	GERP -2.7
Overall
CADD	6.687	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0473% South Asian · 42/88,814 alleles

Filtering AF 0.0359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0319%

Overall 0.00304% 48/1,580,858 alleles · ultra-rare exomes 46/1,428,722 · genomes 2/152,136 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0473%	2,115
Remaining individualsnot grpmax-eligible	0.00325%	30,769
Admixed American	0.00173%	57,742
European (non-Finnish)	0.000256%	390,637

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.Pro554=
Coding: c.1662G>A
MANE Select: NM_020433
dbSNP: rs748323930
Type: single nucleotide variant
Location: chr20:44116013 (GRCh38)
Gene constraint: LOEUF 1.051 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.09 · 2 PDB
Residue 554: 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.Pro554Leu 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
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-pro554 (accessed [today's date]).

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