Is MAG p.Ser448= (c.1344G>A) pathogenic?

MAG p.Ser448= (c.1344G>A) is classified Likely benign in MAG (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-31). Ultra-rare (popmax 0.0397%, nfe); Associated with hereditary spastic paraplegia 75.

What condition is associated with MAG p.Ser448= (c.1344G>A)?

MAG p.Ser448= (c.1344G>A) is associated with hereditary spastic paraplegia 75 (ClinVar).

How common is MAG p.Ser448= (c.1344G>A) in the general population?

MAG p.Ser448= (c.1344G>A) is ultra-rare (popmax 0.0397%, nfe) (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.Ser448=

c.1344G>A · rs149838575 · VCV542303

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0397%, nfe)

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 -8.2	GERP -4.6
Overall
CADD	0.062	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0397% European (non-Finnish) · 469/1,179,946 alleles

Filtering AF 0.0367% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0355%

Overall 0.0305% 493/1,614,046 alleles · ultra-rare exomes 456/1,461,670 · genomes 37/152,376 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0397%	2,516
Remaining individualsnot grpmax-eligible	0.0208%	4,808
Admixed American	0.015%	6,670
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,594
Finnishnot grpmax-eligible	0.00156%	63,962

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.Ser448=
Coding: c.1344G>A
MANE Select: NM_002361
dbSNP: rs149838575
Type: single nucleotide variant
Location: chr19:35309986 (GRCh38)
Gene constraint: LOEUF 0.734 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.53
Residue 448: the ig-like c2-type 4 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-ser448 (accessed [today's date]).

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