Is JADE2 p.Pro717Ser (c.2149C>T) pathogenic?

JADE2 p.Pro717Ser (c.2149C>T) is classified Uncertain significance in JADE2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-26). AlphaMissense: likely benign (0.0696); Ultra-rare (popmax 0.049%, eas).

How common is JADE2 p.Pro717Ser (c.2149C>T) in the general population?

JADE2 p.Pro717Ser (c.2149C>T) is ultra-rare (popmax 0.049%, eas) (gnomAD).

What do computational predictors say about JADE2 p.Pro717Ser (c.2149C>T)?

AlphaMissense predicts likely benign (score 0.0696) — an in-silico prediction, not a clinical call.

JADE2 p.Pro717Ser

c.2149C>T · rs377697968 · VCV2508900

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0696 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.049%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0696	likely benign
REVEL	0.075	moderately benign-leaning
SaProt	LLR -6.37	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 1	GERP 0.98, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 636 bp · p 0.97 · regional, not allelic
Overall
CADD	14.57	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 P673S vs ClinVar P717S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.049% East Asian · 22/44,892 alleles

Filtering AF 0.0331% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0279%

Overall 0.00223% 36/1,613,100 alleles · ultra-rare exomes 27/1,460,882 · genomes 9/152,218 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.049%	2,041
Remaining individualsnot grpmax-eligible	0.0096%	10,411
African / African-American	0.004%	24,983
South Asian	0.0022%	45,515
European (non-Finnish)	0.000254%	393,290

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.Pro717Ser
Coding: c.2149C>T
MANE Select: NM_001388185
dbSNP: rs377697968
Type: single nucleotide variant
Location: chr5:134578961 (GRCh38)
Gene constraint: LOEUF 0.25 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 62.79
Residue 673 UniProt numbering: the 'disordered' region

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

Similar variants

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
JADE2 p.Arg136His 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-pro717ser (accessed [today's date]).

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