Is SPAST p.Pro19Ala (c.55C>G) pathogenic?

SPAST p.Pro19Ala (c.55C>G) is classified Likely pathogenic in SPAST (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-04). AlphaMissense: likely benign (0.0509); Absent from gnomAD v4.1; Associated with hereditary spastic paraplegia 4.

What condition is associated with SPAST p.Pro19Ala (c.55C>G)?

SPAST p.Pro19Ala (c.55C>G) is associated with hereditary spastic paraplegia 4 (ClinVar).

How common is SPAST p.Pro19Ala (c.55C>G) in the general population?

SPAST p.Pro19Ala (c.55C>G) is absent from gnomAD v4.1 (gnomAD).

How is Autosomal dominant spastic paraplegia type 4 inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about SPAST p.Pro19Ala (c.55C>G)?

AlphaMissense predicts likely benign (score 0.0509) — an in-silico prediction, not a clinical call.

SPAST p.Pro19Ala

c.55C>G · rs372349942 · VCV1810212

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0509 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

hereditary spastic paraplegia 4

Computational evidence

Protein change
AlphaMissense	0.0509	likely benign ⚠ discordant with ClinVar
REVEL	0.317	indeterminate
SaProt	LLR -6.75	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 3.2	GERP 1.9, phastCons 1
Regional constraint	o/e 1.22	unconstrained · MANE · 52 kb · p 3.5e-06 · regional, not allelic
Overall
CADD	18.14	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.Pro19Ala
Coding: c.55C>G
MANE Select: NM_014946
dbSNP: rs372349942
Type: single nucleotide variant
Location: chr2:32063886 (GRCh38)
Gene constraint: LOEUF 0.69 · pLI 0.11 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.03 · 7 PDB
Residue 19: 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

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.Pro19Ser Uncertain significance ★★ ⚠ same residue
SPAST p.Pro19= Likely benign ★ same residue
SPAST p.Pro19Arg Uncertain significance ★ ⚠ same residue
SPAST p.Pro19Leu 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

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-pro19ala (accessed [today's date]).

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