Is SACS p.Arg2425Pro (c.7274G>C) pathogenic?

SACS p.Arg2425Pro (c.7274G>C) is classified Pathogenic in SACS (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-01-01). AlphaMissense: likely pathogenic (0.9984); Absent from gnomAD v4.1; Associated with Charlevoix-Saguenay spastic ataxia.

What condition is associated with SACS p.Arg2425Pro (c.7274G>C)?

SACS p.Arg2425Pro (c.7274G>C) is associated with Charlevoix-Saguenay spastic ataxia (ClinVar).

How common is SACS p.Arg2425Pro (c.7274G>C) in the general population?

SACS p.Arg2425Pro (c.7274G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SACS p.Arg2425Pro (c.7274G>C)?

AlphaMissense predicts likely pathogenic (score 0.9984) — an in-silico prediction, not a clinical call.

SACS p.Arg2425Pro

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.7274G>C · rs771583552 · VCV989212

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9984 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Charlevoix-Saguenay spastic ataxia

Computational evidence

Protein change
AlphaMissense	0.9984	likely pathogenic ✓ concordant with ClinVar · top 2% in SACS
REVEL	0.752	pathogenic-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this damaging; SaProt makes no call.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.7	GERP 1.6, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 76 kb · p 0.00012 · regional, not allelic
Overall
CADD	26.4	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.Arg2425Pro
Coding: c.7274G>C
MANE Select: NM_014363
dbSNP: rs771583552
Type: single nucleotide variant
Location: chr13:23336602 (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 p.Arg2425Ter Pathogenic/Likely pathogenic ★★ same residue
SACS p.Arg2425= Conflicting classifications of pathogenicity ★ same residue
SACS p.Arg2425Gln Likely benign ★ same residue
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

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-arg2425pro (accessed [today's date]).

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