Is MAG p.Pro269= (c.807G>C) pathogenic?

MAG p.Pro269= (c.807G>C) is classified Likely benign in MAG (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-04-01). Ultra-rare (popmax 0.0167%, mid); Associated with hereditary spastic paraplegia 75.

What condition is associated with MAG p.Pro269= (c.807G>C)?

MAG p.Pro269= (c.807G>C) is associated with hereditary spastic paraplegia 75 (ClinVar).

How common is MAG p.Pro269= (c.807G>C) in the general population?

MAG p.Pro269= (c.807G>C) is ultra-rare (popmax 0.0167%, mid) (gnomAD).

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.Pro269=

c.807G>C · rs200687098 · VCV1536886

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0167%, mid)

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 -0.58	GERP -4.3, phastCons 0.002
Overall
CADD	8.694	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0167% Middle Eastern · 1/6,006 alleles

Filtering AF 0.000185% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000121%

Overall 0.000566% 9/1,588,712 alleles · ultra-rare exomes 9/1,436,430 · genomes 0/152,282 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0167%	6,006
Admixed American	0.0017%	58,662
Remaining individualsnot grpmax-eligible	0.00162%	61,552
European (non-Finnish)	0.000513%	194,911

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.Pro269=
Coding: c.807G>C
MANE Select: NM_002361
dbSNP: rs200687098
Type: single nucleotide variant
Location: chr19:35300241 (GRCh38)
Gene constraint: LOEUF 0.734 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.53
Residue 269: the 'interaction with rtn4r and rtn4rl2' region; the ig-like c2-type 2 domain

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.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
MAG p.Arg563Cys Uncertain significance ★★ ⚠ same condition
MAG p.Arg563His 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-pro269 (accessed [today's date]).

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