Is SPAST p.Pro374fs (c.1119del) pathogenic?

SPAST p.Pro374fs (c.1119del) is classified Likely pathogenic in SPAST (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-30). Associated with hereditary spastic paraplegia.

What condition is associated with SPAST p.Pro374fs (c.1119del)?

SPAST p.Pro374fs (c.1119del) is associated with hereditary spastic paraplegia (ClinVar).

SPAST p.Pro374fs

c.1119del · VCV3767889

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

Conditions

hereditary spastic paraplegia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	predicted	premature termination codon in exon 8 of 17
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.6	GERP 1.1, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Variant & gene context

Gene: SPAST
Protein: p.Pro374fs
Coding: c.1119del
MANE Select: NM_014946
Type: Deletion
Location: chr2:32126968 (GRCh38)
Gene constraint: LOEUF 0.69 · pLI 0.11 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.03 · 7 PDB
Residue 374: the 'sufficient for microtubule severing' region; an α-helix; a UniProt-annotated variant site (in spg4)

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

Disease context

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

Similar variants

SPAST c.1493+2_1493+5del Pathogenic/Likely pathogenic ★★ same condition
SPAST p.Ala188fs Pathogenic ★★ same condition
SPAST p.Ala96fs Pathogenic ★★ same condition
SPAST p.Asp321fs Likely pathogenic ★★ same condition
SPAST p.Asn405fs Pathogenic ★ same condition
SPAST p.His120fs Likely pathogenic ★ same condition
SPAST p.Leu131fs Pathogenic ★ same condition
SPAST p.Leu461fs 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-pro374fs (accessed [today's date]).

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