Is SACS p.Ile2575= (c.7725A>T) pathogenic?

SACS p.Ile2575= (c.7725A>T) is classified Conflicting classifications of pathogenicity in SACS (ClinVar, Conflicting submitters, 9 submitters; last evaluated 2026-02-01). Ultra-rare (popmax 0.0893%, nfe); Associated with Charlevoix-Saguenay spastic ataxia.

What condition is associated with SACS p.Ile2575= (c.7725A>T)?

SACS p.Ile2575= (c.7725A>T) is associated with Charlevoix-Saguenay spastic ataxia (ClinVar).

How common is SACS p.Ile2575= (c.7725A>T) in the general population?

SACS p.Ile2575= (c.7725A>T) is ultra-rare (popmax 0.0893%, nfe) (gnomAD).

SACS p.Ile2575=

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.7725A>T · rs200735789 · VCV696439

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 9 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0893%, nfe)

Conditions

Charlevoix-Saguenay spastic ataxia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.62	GERP -3.6, phastCons 1
Overall
CADD	5.453	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0893% European (non-Finnish) · 1,054/1,179,650 alleles

Filtering AF 0.0848% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.083%

Overall 0.069% 1,114/1,613,690 alleles · ultra-rare exomes 1,056/1,461,386 · genomes 58/152,304 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0893%	1,119
Remaining individualsnot grpmax-eligible	0.064%	1,562
Admixed American	0.0167%	5,999
African / African-American	0.0107%	9,379
Finnishnot grpmax-eligible	0.00312%	32,013

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: SACS
Protein: p.Ile2575=
Coding: c.7725A>T
MANE Select: NM_014363
dbSNP: rs200735789
Type: single nucleotide variant
Location: chr13:23336151 (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.Ile2575Arg Uncertain significance ★ ⚠ same residue
SACS p.Ile2575Met Conflicting classifications of pathogenicity ★ same residue
SACS p.Ile2575Thr Uncertain significance ★ ⚠ 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-ile2575 (accessed [today's date]).

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