Is SACS p.Pro461Arg (c.1382C>G) pathogenic?

SACS p.Pro461Arg (c.1382C>G) is classified Uncertain significance in SACS (ClinVar, Single submitter, 1 submitter; last evaluated 2022-02-08). AlphaMissense: likely pathogenic (0.9048); Absent from gnomAD v4.1; Associated with Charlevoix-Saguenay spastic ataxia.

What condition is associated with SACS p.Pro461Arg (c.1382C>G)?

SACS p.Pro461Arg (c.1382C>G) is associated with Charlevoix-Saguenay spastic ataxia (ClinVar).

How common is SACS p.Pro461Arg (c.1382C>G) in the general population?

SACS p.Pro461Arg (c.1382C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SACS p.Pro461Arg (c.1382C>G)?

AlphaMissense predicts likely pathogenic (score 0.9048) — an in-silico prediction, not a clinical call.

SACS p.Pro461Arg

Q: How is Autosomal recessive spastic ataxia of Charlevoix-Saguenay inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.1382C>G · VCV3897031

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9048 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

Charlevoix-Saguenay spastic ataxia

Computational evidence

Protein change
AlphaMissense	0.9048	likely pathogenic
REVEL	0.591	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 76 kb · p 0.00012 · regional, not allelic
Overall
CADD	24.6	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: SACS
Protein: p.Pro461Arg
Coding: c.1382C>G
MANE Select: NM_014363
Type: single nucleotide variant
Location: chr13:23355230 (GRCh38)
Gene constraint: LOEUF 0.644 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)

Full SACS gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Charlevoix-Saguenay spastic ataxia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Autosomal recessive spastic ataxia of Charlevoix-Saguenay (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult, Childhood, Infancy

Similar variants

SACS c.2093+1G>A Likely pathogenic ★★ same condition
SACS c.604+1G>A Likely pathogenic ★★ same condition
SACS p.Ala4074Pro Pathogenic ★★ same condition
SACS p.Arg1575Pro Pathogenic ★★ same condition
SACS p.Arg1645Gln Likely pathogenic ★★ same condition
SACS p.Arg1645Ter Pathogenic ★★ same condition
SACS p.Arg1877Ter Pathogenic/Likely pathogenic ★★ same condition
SACS p.Arg1907Ter Pathogenic ★★ 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/sacs-p-pro461arg (accessed [today's date]).

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