Is MAGEL2 p.Ala1026Val (c.3077C>T) pathogenic?

MAGEL2 p.Ala1026Val (c.3077C>T) is classified Uncertain significance in MAGEL2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-07-22). AlphaMissense: ambiguous (0.4828); Ultra-rare (popmax 0.012%, afr); Associated with MAGEL2-related disorder.

What condition is associated with MAGEL2 p.Ala1026Val (c.3077C>T)?

MAGEL2 p.Ala1026Val (c.3077C>T) is associated with MAGEL2-related disorder (ClinVar).

How common is MAGEL2 p.Ala1026Val (c.3077C>T) in the general population?

MAGEL2 p.Ala1026Val (c.3077C>T) is ultra-rare (popmax 0.012%, afr) (gnomAD).

What do computational predictors say about MAGEL2 p.Ala1026Val (c.3077C>T)?

AlphaMissense predicts ambiguous (score 0.4828) — an in-silico prediction, not a clinical call.

MAGEL2 p.Ala1026Val

c.3077C>T · rs370022000 · VCV2633106

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4828 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.012%, afr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

MAGEL2-related disorder

Computational evidence

Protein change
AlphaMissense	0.4828	ambiguous
REVEL	0.059	moderately benign-leaning
SaProt	LLR -8.91	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 8.9	GERP 0.33, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 3,746 bp · p 0.0015 · regional, not allelic
Overall
CADD	23.0	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 0.012% African / African-American · 9/74,916 alleles

Filtering AF 0.00624% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00468%

Overall 0.00062% 10/1,613,748 alleles · ultra-rare exomes 5/1,461,584 · genomes 5/152,164 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.012%	8,324
Admixed American	0.00167%	59,990

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: MAGEL2
Protein: p.Ala1026Val
Coding: c.3077C>T
MANE Select: NM_019066
dbSNP: rs370022000
Type: single nucleotide variant
Location: chr15:23644666 (GRCh38)
Structure: AlphaFold pLDDT 44.28 · 1 PDB
Residue 1026: the mage domain

Full MAGEL2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

MAGEL2-related disorder

Similar variants

MAGEL2 p.Ala1026Glu Uncertain significance ⚠ same residue
MAGEL2 p.Ala1026Ser Uncertain significance ★ ⚠ same residue
MAGEL2 p.Ala1026= Likely benign ★ same residue
MAGEL2 p.Gln636Ter Pathogenic ★★ same condition
MAGEL2 p.Ala503Thr Uncertain significance ★★ ⚠ same condition
MAGEL2 p.Ala557Gly Uncertain significance ★★ ⚠ same condition
MAGEL2 p.Arg417Cys Uncertain significance ★★ ⚠ same condition
MAGEL2 p.Arg438His 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/magel2-p-ala1026val (accessed [today's date]).

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