Is SPAST p.Pro365Ser (c.1093C>T) pathogenic?

SPAST p.Pro365Ser (c.1093C>T) is classified Uncertain significance in SPAST (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-29). AlphaMissense: likely pathogenic (0.9472); Very rare (popmax 8.52e-05%, nfe).

How common is SPAST p.Pro365Ser (c.1093C>T) in the general population?

SPAST p.Pro365Ser (c.1093C>T) is very rare (popmax 8.52e-05%, nfe) (gnomAD).

What do computational predictors say about SPAST p.Pro365Ser (c.1093C>T)?

AlphaMissense predicts likely pathogenic (score 0.9472) — an in-silico prediction, not a clinical call.

SPAST p.Pro365Ser

c.1093C>T · VCV4528245

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9472 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.52e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9472	likely pathogenic
REVEL	0.864	moderately pathogenic-leaning
SaProt	LLR -13.35	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 7.5	GERP 1.6, phastCons 1
Regional constraint	o/e 0.39	unconstrained · MANE · 26 kb · p 1.7e-17 · regional, not allelic
Overall
CADD	28.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.52e-05% European (non-Finnish) · 1/1,173,872 alleles

Overall 6.22e-05% 1/1,607,008 alleles · very rare exomes 1/1,454,848 · genomes 0/152,160 · 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.Pro365Ser
Coding: c.1093C>T
MANE Select: NM_014946
Type: single nucleotide variant
Location: chr2:32116207 (GRCh38)
Gene constraint: LOEUF 0.69 · pLI 0.11 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.03 · 7 PDB
Residue 365: the 'sufficient for microtubule severing' region; a turn; a UniProt-annotated variant site (in spg4); a UniProt-annotated variant site (in spg4; uncertain significance)

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

Similar variants

SPAST p.Pro365Arg Likely pathogenic ★ same residue
SPAST c.1004+1G>C Pathogenic/Likely pathogenic ★★ same type
SPAST c.1004+1G>T Pathogenic ★★ same type
SPAST c.1004+2T>G Pathogenic ★★ same type
SPAST c.1098+1G>A Pathogenic ★★ same type
SPAST c.1099-1G>A Pathogenic ★★ same type
SPAST c.1099-2A>C Pathogenic/Likely pathogenic ★★ same type
SPAST c.1173+1G>A Pathogenic/Likely pathogenic ★★ same type

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-pro365ser (accessed [today's date]).

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