Is SPAST p.Ala85= (c.255C>T) pathogenic?

SPAST p.Ala85= (c.255C>T) is classified Conflicting classifications of pathogenicity in SPAST (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-09-01). Ultra-rare (popmax 0.0156%, eas); Associated with hereditary spastic paraplegia 4.

What condition is associated with SPAST p.Ala85= (c.255C>T)?

SPAST p.Ala85= (c.255C>T) is associated with hereditary spastic paraplegia 4 (ClinVar).

How common is SPAST p.Ala85= (c.255C>T) in the general population?

SPAST p.Ala85= (c.255C>T) is ultra-rare (popmax 0.0156%, eas) (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.Ala85=

c.255C>T · VCV3369686

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0156%, eas)

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 4.4	GERP 1.1, phastCons 1
Overall
CADD	15.23	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0156% East Asian · 7/44,778 alleles

Filtering AF 0.00727% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00515%

Overall 0.000434% 7/1,611,840 alleles · ultra-rare exomes 7/1,459,600 · genomes 0/152,240 · joint denominator

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.Ala85=
Coding: c.255C>T
MANE Select: NM_014946
Type: single nucleotide variant
Location: chr2:32064086 (GRCh38)
Gene constraint: LOEUF 0.69 · pLI 0.11 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.03 · 7 PDB
Residue 85: the 'required for interaction with ssna1 and microtubules' region; a UniProt-annotated variant site (in spg4); the 'required for interaction with rtn1' region; the 'required for midbody 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.Ala85Ser Uncertain significance ★ ⚠ 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-ala85 (accessed [today's date]).

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