Is MAGEL2 p.Pro175Ser (c.523C>T) pathogenic?

MAGEL2 p.Pro175Ser (c.523C>T) is classified Uncertain significance in MAGEL2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-17). AlphaMissense: likely benign (0.2235); Very rare (popmax 0.00079%, nfe).

How common is MAGEL2 p.Pro175Ser (c.523C>T) in the general population?

MAGEL2 p.Pro175Ser (c.523C>T) is very rare (popmax 0.00079%, nfe) (gnomAD).

What do computational predictors say about MAGEL2 p.Pro175Ser (c.523C>T)?

AlphaMissense predicts likely benign (score 0.2235) — an in-silico prediction, not a clinical call.

MAGEL2 p.Pro175Ser

c.523C>T · VCV3616650

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2235 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00079%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt

Computational evidence

Protein change
AlphaMissense	0.2235	likely benign
SaProt	LLR -10.32	damaging
⇒ SaProt calls this damaging; AlphaMissense does not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 6.2	GERP 0.083, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 3,746 bp · p 0.0015 · regional, not allelic
Overall
CADD	19.04	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; SaProt is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00079% European (non-Finnish) · 9/1,139,342 alleles

Filtering AF 0.000372% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000269%

Overall 0.000591% 9/1,522,870 alleles · very rare exomes 9/1,370,970 · genomes 0/151,900 · joint denominator

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.Pro175Ser
Coding: c.523C>T
MANE Select: NM_019066
Type: single nucleotide variant
Location: chr15:23647220 (GRCh38)
Structure: AlphaFold pLDDT 44.28 · 1 PDB
Residue 175: the 'disordered' region

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

Similar variants

MAGEL2 p.Pro175= Uncertain significance same residue
MAGEL2 p.Pro175del Conflicting classifications of pathogenicity ★ same residue
MAGEL2 p.Arg1187Ter Likely pathogenic ★★ same type
MAGEL2 p.Gln1042Ter Pathogenic ★★ same type
MAGEL2 p.Gln636Ter Pathogenic ★★ same type
MAGEL2 p.Gln638Ter Pathogenic/Likely pathogenic ★★ same type
MAGEL2 p.Gln644Ter Pathogenic/Likely pathogenic ★★ same type
MAGEL2 p.Gln666Ter Pathogenic/Likely pathogenic ★★ 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/magel2-p-pro175ser (accessed [today's date]).

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