Is SPAST p.Glu43= (c.129G>A) pathogenic?

SPAST p.Glu43= (c.129G>A) is classified Likely benign in SPAST (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-29). Absent from gnomAD v4.1; Associated with hereditary spastic paraplegia 4.

What condition is associated with SPAST p.Glu43= (c.129G>A)?

SPAST p.Glu43= (c.129G>A) is associated with hereditary spastic paraplegia 4 (ClinVar).

How common is SPAST p.Glu43= (c.129G>A) in the general population?

SPAST p.Glu43= (c.129G>A) is absent from gnomAD v4.1 (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.Glu43=

c.129G>A · rs542793579 · VCV2148443

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

hereditary spastic paraplegia 4

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.1	GERP -3.6
Overall
CADD	8.216	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: SPAST
Protein: p.Glu43=
Coding: c.129G>A
MANE Select: NM_014946
dbSNP: rs542793579
Type: single nucleotide variant
Location: chr2:32063960 (GRCh38)
Gene constraint: LOEUF 0.69 · pLI 0.11 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.03 · 7 PDB
Residue 43: 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; the 'disordered' 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.Glu43Ter Pathogenic ★ same residue
SPAST p.Glu43Asp Conflicting classifications of pathogenicity ★ ⚠ same residue
SPAST p.Glu43Gln Conflicting classifications of pathogenicity ★ ⚠ 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

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-glu43 (accessed [today's date]).

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