Is SPAST p.Ser44= (c.132G>T) pathogenic?

SPAST p.Ser44= (c.132G>T) is classified Likely benign in SPAST (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-15). Very rare (popmax 0.00334%, amr); Associated with hereditary spastic paraplegia 4.

What condition is associated with SPAST p.Ser44= (c.132G>T)?

SPAST p.Ser44= (c.132G>T) is associated with hereditary spastic paraplegia 4 (ClinVar).

How common is SPAST p.Ser44= (c.132G>T) in the general population?

SPAST p.Ser44= (c.132G>T) is very rare (popmax 0.00334%, amr) (gnomAD).

How is Autosomal dominant spastic paraplegia type 4 inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

SPAST p.Ser44=

c.132G>T · rs1359831787 · VCV2168183

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00334%, amr)

Conditions

hereditary spastic paraplegia 4

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.94	GERP -2.3, phastCons 1
Overall
CADD	11.89	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00334% Admixed American · 2/59,876 alleles

Filtering AF 0.000554% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000248% 4/1,612,056 alleles · very rare exomes 3/1,459,956 · genomes 1/152,100 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00334%	29,938
African / African-American	0.00134%	74,782
European (non-Finnish)	8.48e-05%	1,179,016

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: SPAST
Protein: p.Ser44=
Coding: c.132G>T
MANE Select: NM_014946
dbSNP: rs1359831787
Type: single nucleotide variant
Location: chr2:32063963 (GRCh38)
Gene constraint: LOEUF 0.69 · pLI 0.11 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.03 · 7 PDB
Residue 44: a UniProt-annotated variant site (in spg4); a UniProt-annotated variant site (acts as a disease modifier; patients carrying a mutated allele of spastin and l-44 on the other allele are affected by severe spastic paraplegia with an early age of onset; may decrease the activity of the alternative promoter which directs the synthesis of isoform 3 and isoform 4); the 'required for interaction with rtn1' region; the 'required for midbody localization' region; the 'required for interaction with atl1' region; the 'required for nuclear localization' region

Full SPAST gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hereditary spastic paraplegia 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Autosomal dominant spastic paraplegia type 4 (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood, Infancy
Prevalence: 1-9 / 1 000 000 (Portugal)

Similar variants

SPAST p.Ser44Ter Pathogenic ★ same residue
SPAST c.1004+1G>C Pathogenic/Likely pathogenic ★★ same condition
SPAST c.1004+1G>T Pathogenic ★★ same condition
SPAST c.1004+2T>G Pathogenic ★★ same condition
SPAST c.1098+1G>A Pathogenic ★★ same condition
SPAST c.1099-1G>A Pathogenic ★★ same condition
SPAST c.1099-2A>C Pathogenic/Likely pathogenic ★★ same condition
SPAST c.1173+1G>A 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/spast-p-ser44 (accessed [today's date]).

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