Is SPAST p.Ala32Pro (c.94G>C) pathogenic?

SPAST p.Ala32Pro (c.94G>C) is classified Uncertain significance in SPAST (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-09). AlphaMissense: likely benign (0.0631); Very rare (popmax 0.000538%, nfe).

How common is SPAST p.Ala32Pro (c.94G>C) in the general population?

SPAST p.Ala32Pro (c.94G>C) is very rare (popmax 0.000538%, nfe) (gnomAD).

What do computational predictors say about SPAST p.Ala32Pro (c.94G>C)?

AlphaMissense predicts likely benign (score 0.0631) — an in-silico prediction, not a clinical call.

SPAST p.Ala32Pro

c.94G>C · VCV3777314

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0631 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000538%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.0631	likely benign
REVEL	0.362	indeterminate
SaProt	LLR -4.84	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.1	GERP -0.16, phastCons 1
Regional constraint	o/e 1.22	unconstrained · MANE · 52 kb · p 3.5e-06 · regional, not allelic
Overall
CADD	21.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.000538% European (non-Finnish) · 6/1,114,494 alleles

Filtering AF 0.000194% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000127%

Overall 0.000395% 6/1,518,114 alleles · very rare exomes 6/1,366,766 · genomes 0/151,348 · 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.Ala32Pro
Coding: c.94G>C
MANE Select: NM_014946
Type: single nucleotide variant
Location: chr2:32063925 (GRCh38)
Gene constraint: LOEUF 0.69 · pLI 0.11 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.03 · 7 PDB
Residue 32: the 'required for interaction with rtn1' region; the 'required for midbody localization' region; the 'required for interaction with atl1' region; the 'required for nuclear localization' region; the 'disordered' region

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

Similar variants

SPAST p.Ala32= Likely benign ★ same residue
SPAST p.Ala32fs 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

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-ala32pro (accessed [today's date]).

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