Is JAG2 p.Pro595Ser (c.1783C>T) pathogenic?

JAG2 p.Pro595Ser (c.1783C>T) is classified Uncertain significance in JAG2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-27). AlphaMissense: likely benign (0.0626); Ultra-rare (popmax 0.0377%, nfe).

How common is JAG2 p.Pro595Ser (c.1783C>T) in the general population?

JAG2 p.Pro595Ser (c.1783C>T) is ultra-rare (popmax 0.0377%, nfe) (gnomAD).

What do computational predictors say about JAG2 p.Pro595Ser (c.1783C>T)?

AlphaMissense predicts likely benign (score 0.0626) — an in-silico prediction, not a clinical call.

JAG2 p.Pro595Ser

c.1783C>T · rs145627661 · VCV2394053

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0626 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0377%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0626	likely benign
REVEL	0.198	benign-leaning
SaProt	LLR -6.47	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 -0.041	GERP -4
Regional constraint	o/e 0.73	unconstrained · MANE · 22 kb · p 3.9e-21 · regional, not allelic
Overall
CADD	0.494	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 0.0377% European (non-Finnish) · 444/1,178,910 alleles

Filtering AF 0.0347% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0336%

Overall 0.0307% 494/1,609,596 alleles · ultra-rare exomes 451/1,457,392 · genomes 43/152,204 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0377%	2,655
Finnishnot grpmax-eligible	0.0322%	3,107
Remaining individualsnot grpmax-eligible	0.0209%	4,789
Admixed American	0.0184%	5,435
African / African-American	0.00534%	18,717
Ashkenazi Jewishnot grpmax-eligible	0.00339%	29,490
South Asian	0.0011%	90,624

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.Pro595Ser
Coding: c.1783C>T
MANE Select: NM_002226
dbSNP: rs145627661
Type: single nucleotide variant
Location: chr14:105149060 (GRCh38)
Gene constraint: LOEUF 0.495 · pLI 0.91 (gnomAD)
Structure: AlphaFold pLDDT 72.90 · 3 PDB
Residue 595: the egf-like 10; atypical 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.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
JAG2 p.Val1147Met 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-pro595ser (accessed [today's date]).

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