Is MAG p.Arg508Ter (c.1522C>T) pathogenic?

MAG p.Arg508Ter (c.1522C>T) is classified Pathogenic/Likely pathogenic in MAG (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-02-16). Very rare (popmax 8.47e-05%, nfe); Associated with hereditary spastic paraplegia 75.

What condition is associated with MAG p.Arg508Ter (c.1522C>T)?

MAG p.Arg508Ter (c.1522C>T) is associated with hereditary spastic paraplegia 75 (ClinVar).

How common is MAG p.Arg508Ter (c.1522C>T) in the general population?

MAG p.Arg508Ter (c.1522C>T) is very rare (popmax 8.47e-05%, 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.Arg508Ter

c.1522C>T · rs2066519362 · VCV976660

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Conditions

hereditary spastic paraplegia 75

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function; NMD-escape possible for C-terminal truncations
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.90 · evaluated, not missing
Constraint at this position
Conservation	phyloP 5.9	GERP 0.37, phastCons 1
Overall
CADD	41.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,179,994 alleles

Overall 6.84e-05% 1/1,461,742 alleles · very rare

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.Arg508Ter
Coding: c.1522C>T
MANE Select: NM_000400 · reported on NM_002361
dbSNP: rs2066519362
Type: single nucleotide variant
Location: chr19:35310549 (GRCh38)
Structure: AlphaFold pLDDT 87.74 · 55 PDB
Residue 508: a turn; 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

MAG p.Arg508fs Uncertain significance ★ same residue
ERCC2 p.Phe508Leu Uncertain significance ★ ⚠ same residue
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

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-arg508ter (accessed [today's date]).

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