Is SACS p.Pro249Ser (c.745C>T) pathogenic?

SACS p.Pro249Ser (c.745C>T) is classified Uncertain significance in SACS (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-06). AlphaMissense: ambiguous (0.4465); Very rare (popmax 0.000763%, nfe); Associated with Spastic paraplegia.

What condition is associated with SACS p.Pro249Ser (c.745C>T)?

SACS p.Pro249Ser (c.745C>T) is associated with Spastic paraplegia (ClinVar).

How common is SACS p.Pro249Ser (c.745C>T) in the general population?

SACS p.Pro249Ser (c.745C>T) is very rare (popmax 0.000763%, nfe) (gnomAD).

What do computational predictors say about SACS p.Pro249Ser (c.745C>T)?

AlphaMissense predicts ambiguous (score 0.4465) — an in-silico prediction, not a clinical call.

SACS p.Pro249Ser

c.745C>T · rs975426652 · VCV2192194

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4465 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000763%, nfe)

Conditions

Spastic paraplegia

Computational evidence

Protein change
AlphaMissense	0.4465	ambiguous
REVEL	0.792	moderately pathogenic-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 76 kb · p 0.00012 · regional, not allelic
Overall
CADD	26.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000763% European (non-Finnish) · 9/1,180,026 alleles

Filtering AF 0.000359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00026%

Overall 0.000616% 9/1,461,884 alleles · very rare

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.Pro249Ser
Coding: c.745C>T
MANE Select: NM_014363
dbSNP: rs975426652
Type: single nucleotide variant
Location: chr13:23355867 (GRCh38)
Gene constraint: LOEUF 0.644 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 249: an α-helix

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

Similar variants

SACS p.Pro249= Likely benign ★ same residue
SACS c.604+1G>A Likely pathogenic ★★ same condition
SACS p.Arg1877Ter Pathogenic/Likely pathogenic ★★ same condition
SACS p.Arg1907Ter Pathogenic ★★ same condition
SACS p.Arg2119Ter Pathogenic ★★ same condition
SACS p.Arg2425Ter Pathogenic/Likely pathogenic ★★ same condition
SACS p.Arg2426Ter Pathogenic/Likely pathogenic ★★ same condition
SACS p.Arg2703Cys 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-pro249ser (accessed [today's date]).

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