Is MAG p.Arg77Leu (c.230G>T) pathogenic?

MAG p.Arg77Leu (c.230G>T) is classified Uncertain significance in MAG (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-02-10). AlphaMissense: likely pathogenic (0.8626); Ultra-rare (popmax 0.0107%, afr); Associated with hereditary spastic paraplegia 75.

What condition is associated with MAG p.Arg77Leu (c.230G>T)?

MAG p.Arg77Leu (c.230G>T) is associated with hereditary spastic paraplegia 75 (ClinVar).

How common is MAG p.Arg77Leu (c.230G>T) in the general population?

MAG p.Arg77Leu (c.230G>T) is ultra-rare (popmax 0.0107%, afr) (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.Arg77Leu (c.230G>T)?

AlphaMissense predicts likely pathogenic (score 0.8626) — an in-silico prediction, not a clinical call.

MAG p.Arg77Leu

c.230G>T · rs140544202 · VCV2055278

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8626 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0107%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary spastic paraplegia 75

Computational evidence

Protein change
AlphaMissense	0.8626	likely pathogenic
REVEL	0.246	benign-leaning
SaProt	LLR -8.10	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 9.8	GERP 2.5, phastCons 1
Overall
CADD	29.3	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

Grpmax group 0.0107% African / African-American · 8/74,854 alleles

Filtering AF 0.00528% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00381%

Overall 0.000744% 12/1,613,614 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0107%	9,357
South Asian	0.0011%	91,072
European (non-Finnish)	0.000254%	393,329

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.Arg77Leu
Coding: c.230G>T
MANE Select: NM_000400 · reported on NM_002361
dbSNP: rs140544202
Type: single nucleotide variant
Location: chr19:35295796 (GRCh38)
Structure: AlphaFold pLDDT 87.74 · 55 PDB
Residue 77: 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.Arg77His Likely benign ★★ same residue
ERCC2 p.Val77Met Uncertain significance ★★ ⚠ same residue
ERCC2 p.Val77Leu Uncertain significance ★ ⚠ same residue
MAG p.Arg77Ser 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

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-arg77leu (accessed [today's date]).

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