Is JPH2 p.Ala233Ser (c.697G>T) pathogenic?

JPH2 p.Ala233Ser (c.697G>T) is classified Uncertain significance in JPH2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-09). AlphaMissense: likely benign (0.0656); Very rare (popmax 0.00137%, afr); Associated with Cardiovascular phenotype.

What condition is associated with JPH2 p.Ala233Ser (c.697G>T)?

JPH2 p.Ala233Ser (c.697G>T) is associated with Cardiovascular phenotype (ClinVar).

How common is JPH2 p.Ala233Ser (c.697G>T) in the general population?

JPH2 p.Ala233Ser (c.697G>T) is very rare (popmax 0.00137%, afr) (gnomAD).

What do computational predictors say about JPH2 p.Ala233Ser (c.697G>T)?

AlphaMissense predicts likely benign (score 0.0656) — an in-silico prediction, not a clinical call.

JPH2 p.Ala233Ser

c.697G>T · VCV3894767

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0656 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00137%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.0656	likely benign
REVEL	0.059	moderately benign-leaning
SaProt	LLR -4.63	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.74	GERP -3
Regional constraint	o/e 0.93	unconstrained · MANE · 72 kb · p 0.022 · regional, not allelic
Overall
CADD	0.163	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 0.00137% African / African-American · 1/72,918 alleles

Filtering AF 2.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000196% 3/1,531,276 alleles · very rare exomes 3/1,379,286 · genomes 0/151,990 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00137%	72,918
European (non-Finnish)	0.000175%	572,004

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.Ala233Ser
Coding: c.697G>T
MANE Select: NM_020433
Type: single nucleotide variant
Location: chr20:44160090 (GRCh38)
Gene constraint: LOEUF 1.051 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.09 · 2 PDB

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-ala233ser (accessed [today's date]).

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