Is JPH2 p.Pro491His (c.1472C>A) pathogenic?

JPH2 p.Pro491His (c.1472C>A) is classified Uncertain significance in JPH2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-14). AlphaMissense: likely benign (0.153); No allele count reported in gnomAD v4.1 (AN 1,391,424); Associated with JPH2-related disorder.

What condition is associated with JPH2 p.Pro491His (c.1472C>A)?

JPH2 p.Pro491His (c.1472C>A) is associated with JPH2-related disorder (ClinVar).

How common is JPH2 p.Pro491His (c.1472C>A) in the general population?

JPH2 p.Pro491His (c.1472C>A) is no allele count reported in gnomAD v4.1 (AN 1,391,424) (gnomAD).

What do computational predictors say about JPH2 p.Pro491His (c.1472C>A)?

AlphaMissense predicts likely benign (score 0.153) — an in-silico prediction, not a clinical call.

JPH2 p.Pro491His

c.1472C>A · rs2515718355 · VCV2633141

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.153 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,391,424)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

JPH2-related disorder

Computational evidence

Protein change
AlphaMissense	0.153	likely benign
REVEL	0.353	indeterminate
SaProt	LLR -8.90	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 0.78, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 72 kb · p 0.022 · regional, not allelic
Overall
CADD	27.2	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 1,391,424). 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.Pro491His
Coding: c.1472C>A
MANE Select: NM_020433
dbSNP: rs2515718355
Type: single nucleotide variant
Location: chr20:44116203 (GRCh38)
Gene constraint: LOEUF 1.051 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.09 · 2 PDB
Residue 491: 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

JPH2-related disorder

Similar variants

JPH2 p.Pro491= Likely benign ★ same residue
JPH2 p.Thr161Lys Pathogenic/Likely pathogenic ★★ same condition
JPH2 p.Gly36Asp Uncertain significance ★★ ⚠ same condition
JPH2 p.Gly3Glu Uncertain significance ★★ ⚠ same condition
JPH2 p.Leu226Met Uncertain significance ★★ ⚠ same condition
JPH2 c.379+8369C>T Likely benign same condition
JPH2 c.379+8370G>A Likely benign same condition
JPH2 p.Arg300Cys Likely benign 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-pro491his (accessed [today's date]).

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