Is MAGED2 p.Arg446Cys (c.1336C>T) pathogenic?

MAGED2 p.Arg446Cys (c.1336C>T) is classified Likely pathogenic in MAGED2 (ClinVar, Single submitter, 2 submitters; last evaluated 2022-11-09). AlphaMissense: likely pathogenic (0.9936); No allele count reported in gnomAD v4.1 (AN 1,211,112); Associated with Bartter disease type 5.

What condition is associated with MAGED2 p.Arg446Cys (c.1336C>T)?

MAGED2 p.Arg446Cys (c.1336C>T) is associated with Bartter disease type 5 (ClinVar).

How common is MAGED2 p.Arg446Cys (c.1336C>T) in the general population?

MAGED2 p.Arg446Cys (c.1336C>T) is no allele count reported in gnomAD v4.1 (AN 1,211,112) (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.Arg446Cys (c.1336C>T)?

AlphaMissense predicts likely pathogenic (score 0.9936) — an in-silico prediction, not a clinical call.

MAGED2 p.Arg446Cys

c.1336C>T · rs878854407 · VCV226034

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9936 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,211,112)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Bartter disease type 5

Computational evidence

Protein change
AlphaMissense	0.9936	likely pathogenic ✓ concordant with ClinVar · top 5% in MAGED2
REVEL	0.404	indeterminate
SaProt	LLR -12.99	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3	GERP 2, phastCons 1
Regional constraint	o/e 0.46	unconstrained · MANE · 4,336 bp · p 1.7e-14 · regional, not allelic
Overall
CADD	25.7	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

No allele count reported in gnomAD v4.1 (AN 1,211,112). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: MAGED2
Protein: p.Arg446Cys
Coding: c.1336C>T
MANE Select: NM_177433
dbSNP: rs878854407
Type: single nucleotide variant
Location: chrX:54814725 (GRCh38)
Structure: AlphaFold pLDDT 59.89
Residue 446: the mage domain; a UniProt-annotated variant site (in barts5; loss of interaction with gnas)

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.Arg446His Uncertain significance ★ ⚠ same residue
MAGED2 p.Pro153Ser Uncertain significance ★★ ⚠ same condition
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

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-arg446cys (accessed [today's date]).

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