Is MAG p.Arg563His (c.1688G>A) pathogenic?

MAG p.Arg563His (c.1688G>A) is classified Uncertain significance in MAG (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-07-26). AlphaMissense: likely benign (0.0995); Ultra-rare (popmax 0.0165%, mid); Associated with hereditary spastic paraplegia 75.

What condition is associated with MAG p.Arg563His (c.1688G>A)?

MAG p.Arg563His (c.1688G>A) is associated with hereditary spastic paraplegia 75 (ClinVar).

How common is MAG p.Arg563His (c.1688G>A) in the general population?

MAG p.Arg563His (c.1688G>A) is ultra-rare (popmax 0.0165%, 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.

What do computational predictors say about MAG p.Arg563His (c.1688G>A)?

AlphaMissense predicts likely benign (score 0.0995) — an in-silico prediction, not a clinical call.

MAG p.Arg563His

c.1688G>A · rs138056630 · VCV1369805

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0995 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary spastic paraplegia 75

Computational evidence

Protein change
AlphaMissense	0.0995	likely benign
REVEL	0.163	moderately benign-leaning
SaProt	LLR -7.29	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.7	GERP 1.2, phastCons 1
Overall
CADD	24.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,078 alleles

Filtering AF 0.00394% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00361%

Overall 0.00403% 65/1,612,810 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,078
European (non-Finnish)	0.005%	19,991
South Asian	0.0033%	30,280
Admixed American	0.00167%	59,884
Remaining individualsnot grpmax-eligible	0.0016%	62,444

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.Arg563His
Coding: c.1688G>A
MANE Select: NM_000400 · reported on NM_002361
dbSNP: rs138056630
Type: single nucleotide variant
Location: chr19:35311989 (GRCh38)
Structure: AlphaFold pLDDT 87.74 · 55 PDB
Residue 563: an α-helix; 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.Arg563Cys Uncertain significance ★★ ⚠ same residue
ERCC2 p.Arg563= Likely benign ★★ same residue
MAG p.Arg563Leu 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

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-arg563his (accessed [today's date]).

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