Is JAG2 p.Pro366Leu (c.1097C>T) pathogenic?

JAG2 p.Pro366Leu (c.1097C>T) is classified Uncertain significance in JAG2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-27). AlphaMissense: likely benign (0.0773); Ultra-rare (popmax 0.0214%, afr).

How common is JAG2 p.Pro366Leu (c.1097C>T) in the general population?

JAG2 p.Pro366Leu (c.1097C>T) is ultra-rare (popmax 0.0214%, afr) (gnomAD).

What do computational predictors say about JAG2 p.Pro366Leu (c.1097C>T)?

AlphaMissense predicts likely benign (score 0.0773) — an in-silico prediction, not a clinical call.

JAG2 p.Pro366Leu

c.1097C>T · rs140813175 · VCV2249063

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0773 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0214%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0773	likely benign
REVEL	0.132	moderately benign-leaning
SaProt	LLR -6.64	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 7.4	GERP 2.2, phastCons 1
Regional constraint	o/e 0.73	unconstrained · MANE · 22 kb · p 3.9e-21 · regional, not allelic
Overall
CADD	24.8	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 0.0214% African / African-American · 16/74,922 alleles

Filtering AF 0.0133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0109%

Overall 0.00217% 35/1,611,258 alleles · ultra-rare exomes 22/1,459,034 · genomes 13/152,224 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0214%	4,683
Admixed American	0.00335%	29,893
Remaining individualsnot grpmax-eligible	0.00321%	31,192
East Asian	0.00223%	44,842
South Asian	0.0011%	90,656
European (non-Finnish)	0.0011%	90,728

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.Pro366Leu
Coding: c.1097C>T
MANE Select: NM_002226
dbSNP: rs140813175
Type: single nucleotide variant
Location: chr14:105151682 (GRCh38)
Gene constraint: LOEUF 0.495 · pLI 0.91 (gnomAD)
Structure: AlphaFold pLDDT 72.90 · 3 PDB
Residue 366: a UniProt-annotated variant site (in lgmdr27); the egf-like 4 domain

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

Similar variants

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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-pro366leu (accessed [today's date]).

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