Is JAG2 p.Arg2Trp (c.4C>T) pathogenic?

JAG2 p.Arg2Trp (c.4C>T) is classified Uncertain significance in JAG2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-21). AlphaMissense: likely pathogenic (0.6394); Very rare (popmax 0.00415%, sas).

How common is JAG2 p.Arg2Trp (c.4C>T) in the general population?

JAG2 p.Arg2Trp (c.4C>T) is very rare (popmax 0.00415%, sas) (gnomAD).

What do computational predictors say about JAG2 p.Arg2Trp (c.4C>T)?

AlphaMissense predicts likely pathogenic (score 0.6394) — an in-silico prediction, not a clinical call.

JAG2 p.Arg2Trp

c.4C>T · VCV3862132

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6394 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00415%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.6394	likely pathogenic
REVEL	0.319	indeterminate
SaProt	LLR -8.02	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.9	GERP -1.5, phastCons 1
Regional constraint	o/e 1.15	unconstrained · MANE · 609 bp · p 0.052 · regional, not allelic
Overall
CADD	22.3	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 0.00415% South Asian · 1/24,118 alleles

Filtering AF 0.000121% ClinGen BA1/BS1 input FAF95, joint · FAF99 8.2e-05%

Overall 0.000645% 6/930,518 alleles · very rare exomes 4/785,620 · genomes 2/144,898 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00415%	24,118
Remaining individualsnot grpmax-eligible	0.0036%	27,794
European (non-Finnish)	0.000516%	193,715

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.Arg2Trp
Coding: c.4C>T
MANE Select: NM_002226
Type: single nucleotide variant
Location: chr14:105168417 (GRCh38)
Gene constraint: LOEUF 0.495 · pLI 0.91 (gnomAD)
Structure: AlphaFold pLDDT 72.90 · 3 PDB

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-arg2trp (accessed [today's date]).

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