Is JPH2 p.Pro672Leu (c.2015C>T) pathogenic?

JPH2 p.Pro672Leu (c.2015C>T) is classified Uncertain significance in JPH2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-29). AlphaMissense: likely pathogenic (0.7555); Very rare (popmax 0.00114%, sas); Associated with Cardiovascular phenotype.

What condition is associated with JPH2 p.Pro672Leu (c.2015C>T)?

JPH2 p.Pro672Leu (c.2015C>T) is associated with Cardiovascular phenotype (ClinVar).

How common is JPH2 p.Pro672Leu (c.2015C>T) in the general population?

JPH2 p.Pro672Leu (c.2015C>T) is very rare (popmax 0.00114%, sas) (gnomAD).

What do computational predictors say about JPH2 p.Pro672Leu (c.2015C>T)?

AlphaMissense predicts likely pathogenic (score 0.7555) — an in-silico prediction, not a clinical call.

JPH2 p.Pro672Leu

c.2015C>T · rs1304425572 · VCV2586441

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7555 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00114%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.7555	likely pathogenic
REVEL	0.493	indeterminate
SaProt	LLR -8.84	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.6, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 72 kb · p 0.022 · regional, not allelic
Overall
CADD	31.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00114% South Asian · 1/87,954 alleles

Overall 0.000125% 2/1,600,822 alleles · very rare exomes 1/1,448,746 · genomes 1/152,076 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00114%	87,954
European (non-Finnish)	8.51e-05%	1,174,584

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.Pro672Leu
Coding: c.2015C>T
MANE Select: NM_020433
dbSNP: rs1304425572
Type: single nucleotide variant
Location: chr20:44114872 (GRCh38)
Gene constraint: LOEUF 1.051 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.09 · 2 PDB
Residue 672: 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

Similar variants

JPH2 c.-4T>A 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
JPH2 p.Ala401Val Uncertain significance ★★ ⚠ same condition
JPH2 p.Ala419Ser Uncertain significance ★★ ⚠ same condition
JPH2 p.Ala460Val 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-pro672leu (accessed [today's date]).

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