Is SPAST p.Ser588Phe (c.1763C>T) pathogenic?

SPAST p.Ser588Phe (c.1763C>T) is classified Conflicting classifications of pathogenicity in SPAST (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-12-30). AlphaMissense: likely pathogenic (0.9987); Absent from gnomAD v4.1; Associated with SPAST-related disorder.

What condition is associated with SPAST p.Ser588Phe (c.1763C>T)?

SPAST p.Ser588Phe (c.1763C>T) is associated with SPAST-related disorder (ClinVar).

How common is SPAST p.Ser588Phe (c.1763C>T) in the general population?

SPAST p.Ser588Phe (c.1763C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SPAST p.Ser588Phe (c.1763C>T)?

AlphaMissense predicts likely pathogenic (score 0.9987) — an in-silico prediction, not a clinical call.

SPAST p.Ser588Phe

c.1763C>T · VCV4682174

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9987 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

SPAST-related disorder

Computational evidence

Protein change
AlphaMissense	0.9987	likely pathogenic · top 5% in SPAST
REVEL	0.909	moderately pathogenic-leaning
SaProt	LLR -14.83	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.7, phastCons 1
Regional constraint	o/e 0.75	unconstrained · MANE · 13 kb · p 0.0051 · regional, not allelic
Overall
CADD	29.3	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

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.Ser588Phe
Coding: c.1763C>T
MANE Select: NM_014946
Type: single nucleotide variant
Location: chr2:32154408 (GRCh38)
Gene constraint: LOEUF 0.69 · pLI 0.11 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.03 · 7 PDB
Residue 588: a UniProt-annotated variant site (in spg4); the 'sufficient for microtubule severing' region; an α-helix

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

Disease context

SPAST-related disorder

Similar variants

SPAST p.Ser588Pro Conflicting classifications of pathogenicity ★ ⚠ same residue
SPAST c.1004+1G>C Pathogenic/Likely pathogenic ★★ same condition
SPAST c.1245+1G>A Pathogenic ★★ same condition
SPAST c.1245+1G>T Pathogenic ★★ same condition
SPAST c.1413+5G>A Pathogenic/Likely pathogenic ★★ same condition
SPAST c.1688-1G>A Pathogenic/Likely pathogenic ★★ same condition
SPAST c.1728+2T>G Pathogenic/Likely pathogenic ★★ same condition
SPAST c.870+1G>T 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-ser588phe (accessed [today's date]).

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