Is JPH2 p.Pro575Leu (c.1724C>T) pathogenic?

JPH2 p.Pro575Leu (c.1724C>T) is classified Uncertain significance in JPH2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2023-06-29). AlphaMissense: likely benign (0.1092); Very rare (popmax 0.00227%, sas); Associated with hypertrophic cardiomyopathy.

What condition is associated with JPH2 p.Pro575Leu (c.1724C>T)?

JPH2 p.Pro575Leu (c.1724C>T) is associated with hypertrophic cardiomyopathy (ClinVar).

How common is JPH2 p.Pro575Leu (c.1724C>T) in the general population?

JPH2 p.Pro575Leu (c.1724C>T) is very rare (popmax 0.00227%, sas) (gnomAD).

What do computational predictors say about JPH2 p.Pro575Leu (c.1724C>T)?

AlphaMissense predicts likely benign (score 0.1092) — an in-silico prediction, not a clinical call.

JPH2 p.Pro575Leu

c.1724C>T · rs1310645221 · VCV452998

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1092 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00227%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hypertrophic cardiomyopathy

Computational evidence

Protein change
AlphaMissense	0.1092	likely benign
REVEL	0.204	benign-leaning
SaProt	LLR -6.98	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 7.7	GERP 1.7, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 72 kb · p 0.022 · regional, not allelic
Overall
CADD	22.9	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 0.00227% South Asian · 2/88,090 alleles

Filtering AF 0.000377% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000141%

Overall 0.000255% 4/1,569,698 alleles · very rare exomes 4/1,417,460 · genomes 0/152,238 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00227%	44,045
Remaining individualsnot grpmax-eligible	0.00163%	61,202
European (non-Finnish)	8.58e-05%	1,164,892

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.Pro575Leu
Coding: c.1724C>T
MANE Select: NM_020433
dbSNP: rs1310645221
Type: single nucleotide variant
Location: chr20:44115951 (GRCh38)
Gene constraint: LOEUF 1.051 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.09 · 2 PDB
Residue 575: 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.Pro575= Likely benign ★ 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-pro575leu (accessed [today's date]).

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