Is JPH2 p.Ser517Arg (c.1551C>A) pathogenic?

JPH2 p.Ser517Arg (c.1551C>A) is classified Uncertain significance in JPH2 (ClinVar, Single submitter, 3 submitters; last evaluated 2019-03-01). AlphaMissense: likely benign (0.1272); Very rare (popmax 0.00305%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with JPH2 p.Ser517Arg (c.1551C>A)?

JPH2 p.Ser517Arg (c.1551C>A) is associated with Cardiovascular phenotype (ClinVar).

How common is JPH2 p.Ser517Arg (c.1551C>A) in the general population?

JPH2 p.Ser517Arg (c.1551C>A) is very rare (popmax 0.00305%, nfe) (gnomAD).

What do computational predictors say about JPH2 p.Ser517Arg (c.1551C>A)?

AlphaMissense predicts likely benign (score 0.1272) — an in-silico prediction, not a clinical call.

JPH2 p.Ser517Arg

c.1551C>A · rs1295638660 · VCV1284668

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1272 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00305%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.1272	likely benign
REVEL	0.021	moderately benign-leaning
SaProt	LLR -6.30	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 -0.36	GERP -1.4
Regional constraint	o/e 0.93	unconstrained · MANE · 72 kb · p 0.022 · regional, not allelic
Overall
CADD	6.106	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 0.00305% European (non-Finnish) · 34/1,113,786 alleles

Filtering AF 0.0022% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00194%

Overall 0.00241% 35/1,453,670 alleles · very rare exomes 35/1,301,520 · genomes 0/152,150 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00305%	32,758
South Asian	0.00142%	70,574

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.Ser517Arg
Coding: c.1551C>A
MANE Select: NM_020433
dbSNP: rs1295638660
Type: single nucleotide variant
Location: chr20:44116124 (GRCh38)
Gene constraint: LOEUF 1.051 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.09 · 2 PDB
Residue 517: 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

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

JPH2 p.Ser517= Likely benign ★★ same residue
JPH2 p.Ser517Asn Uncertain significance ★ ⚠ same residue
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

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-ser517arg (accessed [today's date]).

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