Is JAG2 p.Pro451Ser (c.1351C>T) pathogenic?

JAG2 p.Pro451Ser (c.1351C>T) is classified Uncertain significance in JAG2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-30). AlphaMissense: likely benign (0.1111); Very rare (popmax 0.00833%, amr).

How common is JAG2 p.Pro451Ser (c.1351C>T) in the general population?

JAG2 p.Pro451Ser (c.1351C>T) is very rare (popmax 0.00833%, amr) (gnomAD).

What do computational predictors say about JAG2 p.Pro451Ser (c.1351C>T)?

AlphaMissense predicts likely benign (score 0.1111) — an in-silico prediction, not a clinical call.

JAG2 p.Pro451Ser

c.1351C>T · VCV4089165

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1111 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00833%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1111	likely benign
REVEL	0.587	indeterminate
SaProt	LLR -8.45	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 9.9	GERP 2.2, phastCons 1
Regional constraint	o/e 0.73	unconstrained · MANE · 22 kb · p 3.9e-21 · regional, not allelic
Overall
CADD	24.7	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 0.00833% Admixed American · 5/60,000 alleles

Filtering AF 0.00323% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00207%

Overall 0.000496% 8/1,613,030 alleles · very rare exomes 8/1,460,698 · genomes 0/152,332 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00833%	12,000
European (non-Finnish)	0.000254%	393,275

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: JAG2
Protein: p.Pro451Ser
Coding: c.1351C>T
MANE Select: NM_002226
Type: single nucleotide variant
Location: chr14:105151021 (GRCh38)
Gene constraint: LOEUF 0.495 · pLI 0.91 (gnomAD)
Structure: AlphaFold pLDDT 72.90 · 3 PDB
Residue 451: the egf-like 6; calcium-binding domain; a UniProt-annotated variant site (in lgmdr27)

Full JAG2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

JAG2 p.Pro451Leu Uncertain significance ★ ⚠ same residue
JAG2 p.Gly839Arg Likely pathogenic ★★ same type
JAG2 p.Arg466His Uncertain significance ★★ ⚠ same type
JAG2 p.Arg686His Uncertain significance ★★ ⚠ same type
JAG2 p.Arg979Cys Uncertain significance ★★ ⚠ same type
JAG2 p.Gly994Arg Uncertain significance ★★ ⚠ same type
JAG2 p.Pro1130Leu Uncertain significance ★★ ⚠ same type
JAG2 p.Pro157Leu Uncertain significance ★★ ⚠ same type

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/jag2-p-pro451ser (accessed [today's date]).

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