Is MAG p.Phe523Ser (c.1568T>C) pathogenic?

MAG p.Phe523Ser (c.1568T>C) is classified Uncertain significance in MAG (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-13). AlphaMissense: likely pathogenic (0.9818); Absent from gnomAD v4.1; Associated with hereditary spastic paraplegia 75.

What condition is associated with MAG p.Phe523Ser (c.1568T>C)?

MAG p.Phe523Ser (c.1568T>C) is associated with hereditary spastic paraplegia 75 (ClinVar).

How common is MAG p.Phe523Ser (c.1568T>C) in the general population?

MAG p.Phe523Ser (c.1568T>C) is absent from gnomAD v4.1 (gnomAD).

How is Autosomal recessive spastic paraplegia type 75 inherited?

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

What do computational predictors say about MAG p.Phe523Ser (c.1568T>C)?

AlphaMissense predicts likely pathogenic (score 0.9818) — an in-silico prediction, not a clinical call.

MAG p.Phe523Ser

c.1568T>C · rs2513601278 · VCV2099989

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9818 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary spastic paraplegia 75

Computational evidence

Protein change
AlphaMissense	0.9818	likely pathogenic
REVEL	0.251	benign-leaning
SaProt	LLR -6.60	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 1.6, phastCons 1
Overall
CADD	24.5	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: MAG
Protein: p.Phe523Ser
Coding: c.1568T>C
MANE Select: NM_000400 · reported on NM_002361
dbSNP: rs2513601278
Type: single nucleotide variant
Location: chr19:35310595 (GRCh38)
Structure: AlphaFold pLDDT 87.74 · 55 PDB
Residue 523: an α-helix; the 'mediates interaction with mms19' region

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

Disease context

hereditary spastic paraplegia 75 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Autosomal recessive spastic paraplegia type 75 (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood

Similar variants

ERCC2 p.Leu523Phe Uncertain significance ★ ⚠ same residue
ERCC2 p.Leu523Val Uncertain significance ★ ⚠ same residue
ERCC2 p.Leu523= Likely benign ★ same residue
MAG p.Arg508Ter Pathogenic/Likely pathogenic ★★ same condition
MAG p.Ala307Val Uncertain significance ★★ ⚠ same condition
MAG p.Ala490Thr Uncertain significance ★★ ⚠ same condition
MAG p.Arg316Leu Uncertain significance ★★ ⚠ same condition
MAG p.Arg425Gln 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/mag-p-phe523ser (accessed [today's date]).

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