Is MAG p.Ser133= (c.399C>T) pathogenic?

MAG p.Ser133= (c.399C>T) is classified Benign in MAG (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-04). Common (popmax 42.1%, eas) — too common for a highly-penetrant pathogenic allele; Associated with hereditary spastic paraplegia 75.

What condition is associated with MAG p.Ser133= (c.399C>T)?

MAG p.Ser133= (c.399C>T) is associated with hereditary spastic paraplegia 75 (ClinVar).

How is Autosomal recessive spastic paraplegia type 75 inherited?

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

MAG p.Ser133=

Q: How common is MAG p.Ser133= (c.399C>T) in the general population?

MAG p.Ser133= (c.399C>T) is common (popmax 42.1%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.399C>T · rs2301600 · VCV1168325

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Common

common (popmax 42.1%, eas) — too common for a highly-penetrant pathogenic allele

Conditions

hereditary spastic paraplegia 75

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.3	GERP -0.94, phastCons 0.11
Overall
CADD	11.83	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 42.1% East Asian · 18,783/44,586 alleles

Filtering AF 41.6% ClinGen BA1/BS1 input FAF95, joint · FAF99 41.4%

Overall 23.9% 379,797/1,590,544 alleles · common

Ancestry group	Frequency	1 in
East Asiangrpmax	42.1%	2
Admixed American	36.2%	3
South Asian	35.7%	3
Remaining individualsnot grpmax-eligible	24.6%	4
Ashkenazi Jewishnot grpmax-eligible	22.8%	4
European (non-Finnish)	22.5%	4
Middle Eastern	22.5%	4
Finnishnot grpmax-eligible	21.9%	5
Amishnot grpmax-eligible	18.8%	5
African / African-American	12.2%	8

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: MAG
Protein: p.Ser133=
Coding: c.399C>T
MANE Select: NM_000400 · reported on NM_002361
dbSNP: rs2301600
Type: single nucleotide variant
Location: chr19:35295965 (GRCh38)
Structure: AlphaFold pLDDT 87.74 · 55 PDB
Residue 133: the helicase atp-binding domain; an α-helix

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

MAG p.Ser133Arg Pathogenic ⚠ same residue
ERCC2 p.Lys133Arg Uncertain significance ★ ⚠ 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
MAG p.Arg465His 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-ser133 (accessed [today's date]).

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