Is JAG2 p.Pro682Ser (c.2044C>T) pathogenic?

JAG2 p.Pro682Ser (c.2044C>T) is classified Conflicting classifications of pathogenicity in JAG2 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-08-22). AlphaMissense: ambiguous (0.3996); Ultra-rare (popmax 0.0733%, amr); Associated with muscular dystrophy, limb-girdle, autosomal recessive 27.

What condition is associated with JAG2 p.Pro682Ser (c.2044C>T)?

JAG2 p.Pro682Ser (c.2044C>T) is associated with muscular dystrophy, limb-girdle, autosomal recessive 27 (ClinVar).

How common is JAG2 p.Pro682Ser (c.2044C>T) in the general population?

JAG2 p.Pro682Ser (c.2044C>T) is ultra-rare (popmax 0.0733%, amr) (gnomAD).

What do computational predictors say about JAG2 p.Pro682Ser (c.2044C>T)?

AlphaMissense predicts ambiguous (score 0.3996) — an in-silico prediction, not a clinical call.

JAG2 p.Pro682Ser

c.2044C>T · rs200708284 · VCV1300194

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.3996 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0733%, amr)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

muscular dystrophy, limb-girdle, autosomal recessive 27

Computational evidence

Protein change
AlphaMissense	0.3996	ambiguous
REVEL	0.872	moderately pathogenic-leaning
SaProt	LLR -12.50	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.32 · evaluated, not missing
Constraint at this position
Conservation	phyloP 11	GERP 2, phastCons 1
Regional constraint	o/e 0.73	unconstrained · MANE · 22 kb · p 3.9e-21 · regional, not allelic
Overall
CADD	29.6	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0733% Admixed American · 44/59,988 alleles

Filtering AF 0.0561% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0501%

Overall 0.0172% 278/1,611,964 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0733%	1,363
Finnishnot grpmax-eligible	0.0223%	4,475
Remaining individualsnot grpmax-eligible	0.0192%	5,200
European (non-Finnish)	0.0175%	5,725
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,560
African / African-American	0.00133%	75,022

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.Pro682Ser
Coding: c.2044C>T
MANE Select: NM_002226
dbSNP: rs200708284
Type: single nucleotide variant
Location: chr14:105148416 (GRCh38)
Gene constraint: LOEUF 0.495 · pLI 0.91 (gnomAD)
Structure: AlphaFold pLDDT 72.90 · 3 PDB
Residue 682: the egf-like 12; calcium-binding domain; a disulfide bond; a UniProt-annotated variant site (in lgmdr27); a UniProt-annotated variant site (in lgmdr27; uncertain significance)

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

Disease context

muscular dystrophy, limb-girdle, autosomal recessive 27 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

JAG2 p.Gly839Arg Likely pathogenic ★★ same condition
JAG2 p.Arg165Ter Likely pathogenic ★ same condition
JAG2 p.Gly281Cys Likely pathogenic ★ same condition
JAG2 p.Tyr104Ter Likely pathogenic ★ same condition
JAG2 p.Ala243Asp Uncertain significance ★ ⚠ same condition
JAG2 p.Arg712Cys Conflicting classifications of pathogenicity ★ ⚠ same condition
JAG2 p.Arg735Cys Uncertain significance ★ ⚠ same condition
JAG2 p.Arg784Cys 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/jag2-p-pro682ser (accessed [today's date]).

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