Is JADE2 p.Pro606Ala (c.1816C>G) pathogenic?

JADE2 p.Pro606Ala (c.1816C>G) is classified Uncertain significance in JADE2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-16). AlphaMissense: likely benign (0.053); Very rare (popmax 0.00102%, nfe).

How common is JADE2 p.Pro606Ala (c.1816C>G) in the general population?

JADE2 p.Pro606Ala (c.1816C>G) is very rare (popmax 0.00102%, nfe) (gnomAD).

What do computational predictors say about JADE2 p.Pro606Ala (c.1816C>G)?

AlphaMissense predicts likely benign (score 0.053) — an in-silico prediction, not a clinical call.

JADE2 p.Pro606Ala

c.1816C>G · VCV4830314

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.053 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00102%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.053	likely benign
REVEL	0.042	moderately benign-leaning
SaProt	LLR -6.20	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 2.1	GERP 1.1, phastCons 0.97
Regional constraint	o/e 0.73	unconstrained · MANE · 4,994 bp · p 0.00046 · regional, not allelic
Overall
CADD	15.06	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 P562A vs ClinVar P606A) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00102% European (non-Finnish) · 12/1,180,040 alleles

Filtering AF 0.000542% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000428%

Overall 0.000867% 14/1,614,150 alleles · very rare exomes 14/1,461,820 · genomes 0/152,330 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0032%	31,253
European (non-Finnish)grpmax	0.00102%	98,337

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro606Ala
Coding: c.1816C>G
MANE Select: NM_001388185
Type: single nucleotide variant
Location: chr5:134578628 (GRCh38)
Gene constraint: LOEUF 0.25 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 62.79

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-pro606ala (accessed [today's date]).

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