Is SACS p.Ser69Ala (c.205T>G) pathogenic?

SACS p.Ser69Ala (c.205T>G) is classified Likely benign in SACS (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-21). AlphaMissense: likely benign (0.07); Ultra-rare (popmax 0.0165%, mid); Associated with Spastic paraplegia.

What condition is associated with SACS p.Ser69Ala (c.205T>G)?

SACS p.Ser69Ala (c.205T>G) is associated with Spastic paraplegia (ClinVar).

How common is SACS p.Ser69Ala (c.205T>G) in the general population?

SACS p.Ser69Ala (c.205T>G) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about SACS p.Ser69Ala (c.205T>G)?

AlphaMissense predicts likely benign (score 0.07) — an in-silico prediction, not a clinical call.

SACS p.Ser69Ala

c.205T>G · rs749794993 · VCV2713046

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.07 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Spastic paraplegia

Computational evidence

Protein change
AlphaMissense	0.07	likely benign
REVEL	0.128	moderately 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 2.9	GERP 0.44, phastCons 0.81
Regional constraint	o/e 0.93	unconstrained · MANE · 76 kb · p 0.00012 · regional, not allelic
Overall
CADD	9.863	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 0.0165% Middle Eastern · 1/6,078 alleles

Filtering AF 0.00437% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00313%

Overall 0.000558% 9/1,612,138 alleles · ultra-rare exomes 8/1,459,900 · genomes 1/152,238 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,078
South Asian	0.0088%	11,367

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.Ser69Ala
Coding: c.205T>G
MANE Select: NM_014363
dbSNP: rs749794993
Type: single nucleotide variant
Location: chr13:23371132 (GRCh38)
Gene constraint: LOEUF 0.644 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 69: the ubiquitin-like domain

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.Ser69= 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-ser69ala (accessed [today's date]).

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