Is SACS p.Pro536= (c.1608G>A) pathogenic?

SACS p.Pro536= (c.1608G>A) is classified Conflicting classifications of pathogenicity in SACS (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-02-01). Ultra-rare (popmax 0.0209%, sas); Associated with Spastic paraplegia.

What condition is associated with SACS p.Pro536= (c.1608G>A)?

SACS p.Pro536= (c.1608G>A) is associated with Spastic paraplegia, Charlevoix-Saguenay spastic ataxia (ClinVar).

How common is SACS p.Pro536= (c.1608G>A) in the general population?

SACS p.Pro536= (c.1608G>A) is ultra-rare (popmax 0.0209%, sas) (gnomAD).

SACS p.Pro536=

c.1608G>A · rs745730439 · VCV311561

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0209%, sas)

Conditions

Spastic paraplegia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.251	benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -11	GERP -3.9
Overall
CADD	0.188	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0209% South Asian · 19/91,094 alleles

Filtering AF 0.0136% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0114%

Overall 0.00328% 53/1,614,114 alleles · ultra-rare exomes 49/1,461,878 · genomes 4/152,236 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0209%	4,794
Remaining individualsnot grpmax-eligible	0.0048%	20,829
Admixed American	0.00333%	30,005
European (non-Finnish)	0.00237%	42,145
African / African-American	0.00133%	74,940

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.Pro536=
Coding: c.1608G>A
MANE Select: NM_014363
dbSNP: rs745730439
Type: single nucleotide variant
Location: chr13:23355004 (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.Pro536Leu Pathogenic/Likely pathogenic ★★ 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
SACS p.Arg1645Ter Pathogenic ★★ same condition
SACS p.Arg1877Ter Pathogenic/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-pro536 (accessed [today's date]).

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