Is SACS p.Ile3526Val (c.10576A>G) pathogenic?

SACS p.Ile3526Val (c.10576A>G) is classified Conflicting classifications of pathogenicity in SACS (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-08-13). AlphaMissense: likely benign (0.0963); Ultra-rare (popmax 0.0153%, nfe); Associated with Spastic paraplegia.

What condition is associated with SACS p.Ile3526Val (c.10576A>G)?

SACS p.Ile3526Val (c.10576A>G) is associated with Spastic paraplegia, Charlevoix-Saguenay spastic ataxia (ClinVar).

How common is SACS p.Ile3526Val (c.10576A>G) in the general population?

SACS p.Ile3526Val (c.10576A>G) is ultra-rare (popmax 0.0153%, nfe) (gnomAD).

What do computational predictors say about SACS p.Ile3526Val (c.10576A>G)?

AlphaMissense predicts likely benign (score 0.0963) — an in-silico prediction, not a clinical call.

SACS p.Ile3526Val

c.10576A>G · rs199881455 · VCV311511

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0963 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0153%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Spastic paraplegia

Computational evidence

Protein change
AlphaMissense	0.0963	likely benign
REVEL	0.223	benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.98	GERP -2.2, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 2,445 bp · p 0.00031 · regional, not allelic
Overall
CADD	11.77	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

Grpmax group 0.0153% European (non-Finnish) · 180/1,177,246 alleles

Filtering AF 0.0134% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0127%

Overall 0.0124% 199/1,605,060 alleles · ultra-rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0193%	5,176
European (non-Finnish)grpmax	0.0153%	6,540
Finnishnot grpmax-eligible	0.00784%	12,763
African / African-American	0.00269%	37,203

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ile3526Val
Coding: c.10576A>G
MANE Select: NM_014363
dbSNP: rs199881455
Type: single nucleotide variant
Location: chr13:23333300 (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

Spastic paraplegia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Charlevoix-Saguenay spastic ataxia

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-ile3526val (accessed [today's date]).

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