Is SACS p.Ser554Arg (c.1662C>A) pathogenic?

SACS p.Ser554Arg (c.1662C>A) is classified Likely benign in SACS (ClinVar, Single submitter, 2 submitters; last evaluated 2024-03-24). AlphaMissense: likely benign (0.0936); Very rare (popmax 0.0022%, sas); Associated with Spastic paraplegia.

What condition is associated with SACS p.Ser554Arg (c.1662C>A)?

SACS p.Ser554Arg (c.1662C>A) is associated with Spastic paraplegia, Charlevoix-Saguenay spastic ataxia (ClinVar).

How common is SACS p.Ser554Arg (c.1662C>A) in the general population?

SACS p.Ser554Arg (c.1662C>A) is very rare (popmax 0.0022%, sas) (gnomAD).

What do computational predictors say about SACS p.Ser554Arg (c.1662C>A)?

AlphaMissense predicts likely benign (score 0.0936) — an in-silico prediction, not a clinical call.

SACS p.Ser554Arg

c.1662C>A · rs185812845 · VCV2897675

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0936 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Spastic paraplegia

Computational evidence

Protein change
AlphaMissense	0.0936	likely benign
REVEL	0.032	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 -5.4	GERP -3.9
Regional constraint	o/e 0.93	unconstrained · MANE · 76 kb · p 0.00012 · regional, not allelic
Overall
CADD	0.067	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 0.0022% South Asian · 2/91,090 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000136%

Overall 0.000124% 2/1,614,070 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.Ser554Arg
Coding: c.1662C>A
MANE Select: NM_014363
dbSNP: rs185812845
Type: single nucleotide variant
Location: chr13:23354950 (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.Ser554= 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
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-ser554arg (accessed [today's date]).

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