Is SPAST p.Pro19Ser (c.55C>T) pathogenic?

SPAST p.Pro19Ser (c.55C>T) is classified Uncertain significance in SPAST (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-08-20). AlphaMissense: likely benign (0.0752); Very rare (popmax 0.00134%, afr); Associated with hereditary spastic paraplegia 4.

What condition is associated with SPAST p.Pro19Ser (c.55C>T)?

SPAST p.Pro19Ser (c.55C>T) is associated with hereditary spastic paraplegia 4 (ClinVar).

How common is SPAST p.Pro19Ser (c.55C>T) in the general population?

SPAST p.Pro19Ser (c.55C>T) is very rare (popmax 0.00134%, afr) (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.Pro19Ser (c.55C>T)?

AlphaMissense predicts likely benign (score 0.0752) — an in-silico prediction, not a clinical call.

SPAST p.Pro19Ser

c.55C>T · rs372349942 · VCV335828

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0752 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary spastic paraplegia 4

Computational evidence

Protein change
AlphaMissense	0.0752	likely benign
REVEL	0.285	benign-leaning
SaProt	LLR -6.76	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
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	20.2	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 0.00134% African / African-American · 1/74,380 alleles

Overall 0.000126% 2/1,583,178 alleles · very rare exomes 1/1,431,382 · genomes 1/151,796 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00134%	74,380
European (non-Finnish)	8.56e-05%	1,167,705

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.Pro19Ser
Coding: c.55C>T
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.Pro19Ala Likely pathogenic ★ ⚠ 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-pro19ser (accessed [today's date]).

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