Is MAGED2 p.Pro153Ser (c.457C>T) pathogenic?

MAGED2 p.Pro153Ser (c.457C>T) is classified Uncertain significance in MAGED2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-05-05). AlphaMissense: likely benign (0.0731); Very rare (popmax 0.00316%, nfe); Associated with Bartter disease type 5.

What condition is associated with MAGED2 p.Pro153Ser (c.457C>T)?

MAGED2 p.Pro153Ser (c.457C>T) is associated with Bartter disease type 5 (ClinVar).

How common is MAGED2 p.Pro153Ser (c.457C>T) in the general population?

MAGED2 p.Pro153Ser (c.457C>T) is very rare (popmax 0.00316%, nfe) (gnomAD).

How is Bartter syndrome inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about MAGED2 p.Pro153Ser (c.457C>T)?

AlphaMissense predicts likely benign (score 0.0731) — an in-silico prediction, not a clinical call.

MAGED2 p.Pro153Ser

c.457C>T · rs746508104 · VCV2096189

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0731 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00316%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Bartter disease type 5

Computational evidence

Protein change
AlphaMissense	0.0731	likely benign
REVEL	0.012	strongly benign-leaning
SaProt	LLR -6.25	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.54	GERP -0.19, phastCons 0.081
Regional constraint	o/e 0.88	unconstrained · MANE · 1,781 bp · p 0.078 · regional, not allelic
Overall
CADD	13.72	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.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00316% European (non-Finnish) · 28/887,325 alleles

Filtering AF 0.00219% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00188%

Overall 0.00242% 29/1,197,139 alleles · very rare exomes 29/1,083,562 · genomes 0/113,577 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00316%	31,690
African / African-American	0.00174%	57,340

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: MAGED2
Protein: p.Pro153Ser
Coding: c.457C>T
MANE Select: NM_177433
dbSNP: rs746508104
Type: single nucleotide variant
Location: chrX:54810133 (GRCh38)
Structure: AlphaFold pLDDT 59.89
Residue 153: the 'disordered' region

Full MAGED2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Bartter disease type 5 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Bartter syndrome (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, X-linked recessive
Onset: Adolescent, Adult, Antenatal, Childhood, Infancy, Neonatal
Prevalence: 1-9 / 1 000 000 (Europe)

Similar variants

MAGED2 p.Ala208= Benign ★★ same condition
MAGED2 p.Pro272= Benign/Likely benign ★★ same condition
MAGED2 p.Ser327= Benign ★★ same condition
MAGED2 p.Ser84= Benign ★★ same condition
MAGED2 p.Thr132= Benign ★★ same condition
MAGED2 c.1386+1G>A Likely pathogenic ★ same condition
MAGED2 p.Arg446Cys Likely pathogenic ★ same condition
MAGED2 p.Gln88Ter Pathogenic ★ 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/maged2-p-pro153ser (accessed [today's date]).

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