Is SPAST p.Pro293= (c.879G>A) pathogenic?

SPAST p.Pro293= (c.879G>A) is classified Benign/Likely benign in SPAST (ClinVar, Multiple submitters, 14 submitters; last evaluated 2026-05-01). Low-frequency (popmax 1.47%, nfe); Associated with hereditary spastic paraplegia 4.

What condition is associated with SPAST p.Pro293= (c.879G>A)?

SPAST p.Pro293= (c.879G>A) is associated with hereditary spastic paraplegia 4, hereditary spastic paraplegia (ClinVar).

How common is SPAST p.Pro293= (c.879G>A) in the general population?

SPAST p.Pro293= (c.879G>A) is low-frequency (popmax 1.47%, nfe) (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.Pro293=

c.879G>A · rs145264166 · VCV219840

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 14 submitters

gnomAD v4.1

Rare

low-frequency (popmax 1.47%, nfe)

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 0.67	GERP -1.9, phastCons 0.94
Overall
CADD	12.06	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.47% European (non-Finnish) · 17,234/1,174,802 alleles

Filtering AF 1.45% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.44%

Overall 1.25% 20,070/1,607,230 alleles · low-frequency exomes 18,683/1,455,134 · genomes 1,387/152,096 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	1.93%	52
European (non-Finnish)grpmax	1.47%	68
Remaining individualsnot grpmax-eligible	1.22%	82
Finnishnot grpmax-eligible	0.996%	100
Admixed American	0.77%	130
Amishnot grpmax-eligible	0.439%	228
Middle Eastern	0.248%	403
South Asian	0.246%	406
African / African-American	0.211%	474
East Asian	0.0179%	5,579

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro293=
Coding: c.879G>A
MANE Select: NM_014946
dbSNP: rs145264166
Type: single nucleotide variant
Location: chr2:32115710 (GRCh38)
Gene constraint: LOEUF 0.69 · pLI 0.11 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.03 · 7 PDB
Residue 293: the 'sufficient for microtubule severing' region; the 'required for interaction with microtubules and microtubule severing' region; the 'disordered' region; a UniProt-annotated variant site (in spg4); the 'required for interaction with rtn1' 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

Also linked: hereditary spastic paraplegia

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.Pro293Leu 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
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-pro293 (accessed [today's date]).

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