Is SACS p.Ser2755fs (c.8261dup) pathogenic?

SACS p.Ser2755fs (c.8261dup) is classified Pathogenic/Likely pathogenic in SACS (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-03-21). Very rare (popmax 8.48e-05%, nfe); Associated with Spastic paraplegia.

What condition is associated with SACS p.Ser2755fs (c.8261dup)?

SACS p.Ser2755fs (c.8261dup) is associated with Spastic paraplegia, Charlevoix-Saguenay spastic ataxia (ClinVar).

How common is SACS p.Ser2755fs (c.8261dup) in the general population?

SACS p.Ser2755fs (c.8261dup) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

SACS p.Ser2755fs

c.8261dup · rs2137593625 · VCV1451340

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Conditions

Spastic paraplegia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (10 of 10) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 1.5	GERP -2.5, phastCons 0.98

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,876 alleles

Overall 6.2e-05% 1/1,613,850 alleles · very rare exomes 1/1,461,608 · genomes 0/152,242 · joint denominator

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.Ser2755fs
Coding: c.8261dup
MANE Select: NM_014363
dbSNP: rs2137593625
Type: Duplication
Location: chr13:23335614 (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 p.Ala2180fs Pathogenic/Likely pathogenic ★★ same condition
SACS p.Arg2932fs Pathogenic/Likely pathogenic ★★ same condition
SACS p.Arg3792fs Pathogenic/Likely pathogenic ★★ same condition
SACS p.Asn1094fs Pathogenic/Likely pathogenic ★★ same condition
SACS p.Asn3040fs Pathogenic/Likely pathogenic ★★ same condition
SACS p.Asp1425_Ile1426insAlaTer Pathogenic/Likely pathogenic ★★ same condition
SACS p.Asp2796fs Pathogenic/Likely pathogenic ★★ same condition
SACS p.Glu2280fs 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-ser2755fs (accessed [today's date]).

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