Is SACS p.Arg2425Ter (c.7273C>T) pathogenic?

SACS p.Arg2425Ter (c.7273C>T) is classified Pathogenic/Likely pathogenic in SACS (ClinVar, Multiple submitters, 7 submitters; last evaluated 2025-04-23). Very rare (popmax 0.00401%, afr); Associated with Spastic paraplegia.

What condition is associated with SACS p.Arg2425Ter (c.7273C>T)?

SACS p.Arg2425Ter (c.7273C>T) is associated with Spastic paraplegia, Charlevoix-Saguenay spastic ataxia (ClinVar).

How common is SACS p.Arg2425Ter (c.7273C>T) in the general population?

SACS p.Arg2425Ter (c.7273C>T) is very rare (popmax 0.00401%, afr) (gnomAD).

SACS p.Arg2425Ter

c.7273C>T · rs145766983 · VCV370415

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00401%, afr)

Conditions

Spastic paraplegia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	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 · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.7	GERP -2.8, phastCons 1
Overall
CADD	36.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00401% African / African-American · 3/74,808 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00065%

Overall 0.00118% 19/1,613,212 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00401%	24,936
European (non-Finnish)	0.00136%	73,732

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.Arg2425Ter
Coding: c.7273C>T
MANE Select: NM_014363
dbSNP: rs145766983
Type: single nucleotide variant
Location: chr13:23336603 (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.Arg2425Pro 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-arg2425ter (accessed [today's date]).

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