Is JPH2 p.Pro552Ser (c.1654C>T) pathogenic?

JPH2 p.Pro552Ser (c.1654C>T) is classified Uncertain significance in JPH2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-19). AlphaMissense: likely benign (0.0771); No allele count reported in gnomAD v4.1 (AN 1,580,852); Associated with hypertrophic cardiomyopathy.

What condition is associated with JPH2 p.Pro552Ser (c.1654C>T)?

JPH2 p.Pro552Ser (c.1654C>T) is associated with hypertrophic cardiomyopathy (ClinVar).

How common is JPH2 p.Pro552Ser (c.1654C>T) in the general population?

JPH2 p.Pro552Ser (c.1654C>T) is no allele count reported in gnomAD v4.1 (AN 1,580,852) (gnomAD).

What do computational predictors say about JPH2 p.Pro552Ser (c.1654C>T)?

AlphaMissense predicts likely benign (score 0.0771) — an in-silico prediction, not a clinical call.

JPH2 p.Pro552Ser

c.1654C>T · VCV4705371

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0771 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,580,852)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hypertrophic cardiomyopathy

Computational evidence

Protein change
AlphaMissense	0.0771	likely benign
REVEL	0.085	moderately benign-leaning
SaProt	LLR -7.59	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 7.6	GERP 0.33, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 72 kb · p 0.022 · regional, not allelic
Overall
CADD	18.24	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

No allele count reported in gnomAD v4.1 (AN 1,580,852). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: JPH2
Protein: p.Pro552Ser
Coding: c.1654C>T
MANE Select: NM_020433
Type: single nucleotide variant
Location: chr20:44116021 (GRCh38)
Gene constraint: LOEUF 1.051 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.09 · 2 PDB
Residue 552: 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

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

Similar variants

JPH2 p.Pro552Leu 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
JPH2 p.Ala405Thr 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-pro552ser (accessed [today's date]).

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