Is JADE2 p.Arg751Trp (c.2251C>T) pathogenic?

JADE2 p.Arg751Trp (c.2251C>T) is classified Uncertain significance in JADE2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-08). AlphaMissense: likely benign (0.1973); Ultra-rare (popmax 0.0154%, sas).

How common is JADE2 p.Arg751Trp (c.2251C>T) in the general population?

JADE2 p.Arg751Trp (c.2251C>T) is ultra-rare (popmax 0.0154%, sas) (gnomAD).

What do computational predictors say about JADE2 p.Arg751Trp (c.2251C>T)?

AlphaMissense predicts likely benign (score 0.1973) — an in-silico prediction, not a clinical call.

JADE2 p.Arg751Trp

c.2251C>T · VCV4680346

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1973 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0154%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1973	likely benign
REVEL	0.084	moderately benign-leaning
SaProt	LLR -8.93	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 3	GERP 0.003, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 636 bp · p 0.97 · 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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R707W vs ClinVar R751W) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0154% South Asian · 14/91,080 alleles

Filtering AF 0.00919% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00735%

Overall 0.00173% 28/1,613,990 alleles · ultra-rare exomes 28/1,461,634 · genomes 0/152,356 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0154%	6,506
European (non-Finnish)	0.00119%	84,283

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: JADE2
Protein: p.Arg751Trp
Coding: c.2251C>T
MANE Select: NM_001388185
Type: single nucleotide variant
Location: chr5:134579063 (GRCh38)
Gene constraint: LOEUF 0.25 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 62.79
Residue 707 UniProt numbering: the 'disordered' region

Full JADE2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

JADE2 p.Arg751Gln Uncertain significance ★ ⚠ same residue
JADE2 p.Ala439Asp Uncertain significance ★ ⚠ same type
JADE2 p.Ala439Thr Uncertain significance ★ ⚠ same type
JADE2 p.Ala668Val Uncertain significance ★ ⚠ same type
JADE2 p.Ala677Thr Uncertain significance ★ ⚠ same type
JADE2 p.Ala721Thr Uncertain significance ★ ⚠ same type
JADE2 p.Ala733Thr Uncertain significance ★ ⚠ same type
JADE2 p.Ala744Thr 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/jade2-p-arg751trp (accessed [today's date]).

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