Is SPAST p.Phe403fs (c.1209_1212del) pathogenic?

SPAST p.Phe403fs (c.12091212del) is classified Pathogenic/Likely pathogenic in SPAST (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-06-29). No gnomAD frequency available for this variant; Associated with SPAST-related disorder.

What condition is associated with SPAST p.Phe403fs (c.1209_1212del)?

SPAST p.Phe403fs (c.1209_1212del) is associated with SPAST-related disorder, hereditary spastic paraplegia 4 (ClinVar).

How common is SPAST p.Phe403fs (c.1209_1212del) in the general population?

SPAST p.Phe403fs (c.1209_1212del) is no gnomAD frequency available for this variant (gnomAD).

SPAST p.Phe403fs

c.1209_1212del · rs1553317029 · VCV444492

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Not reported

no gnomAD frequency available for this variant

Conditions

SPAST-related disorder

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 9 of 17
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.098	GERP -1.1, phastCons 0.94

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

Population frequency

dbSNP / gnomAD

No gnomAD frequency available for this variant. This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: SPAST
Protein: p.Phe403fs
Coding: c.1209_1212del
MANE Select: NM_014946
dbSNP: rs1553317029
Type: Deletion
Location: chr2:32128441 (GRCh38)
Gene constraint: LOEUF 0.69 · pLI 0.11 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.03 · 7 PDB
Residue 403: the 'sufficient for microtubule severing' region; a β-strand; a UniProt-annotated variant site (in spg4)

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

Disease context

SPAST-related disorder

Also linked: hereditary spastic paraplegia 4

Similar variants

SPAST c.1174-1del Pathogenic ★★ same condition
SPAST c.1413+3_1413+6del Pathogenic/Likely pathogenic ★★ same condition
SPAST c.1493+2_1493+5del Pathogenic/Likely pathogenic ★★ same condition
SPAST c.(?_1729 Pathogenic ★★ same condition
SPAST p.Ala188fs Pathogenic ★★ same condition
SPAST p.Ala394fs Pathogenic ★★ same condition
SPAST p.Ala96fs Pathogenic ★★ same condition
SPAST p.Gln280fs 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-phe403fs (accessed [today's date]).

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