Is SPAST p.Pro109Arg (c.326C>G) pathogenic?

SPAST p.Pro109Arg (c.326C>G) is classified Uncertain significance in SPAST (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-02-20). AlphaMissense: likely benign (0.1001); Ultra-rare (popmax 0.0212%, mid); Associated with hereditary spastic paraplegia 4.

What condition is associated with SPAST p.Pro109Arg (c.326C>G)?

SPAST p.Pro109Arg (c.326C>G) is associated with hereditary spastic paraplegia 4 (ClinVar).

How common is SPAST p.Pro109Arg (c.326C>G) in the general population?

SPAST p.Pro109Arg (c.326C>G) is ultra-rare (popmax 0.0212%, mid) (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.Pro109Arg (c.326C>G)?

AlphaMissense predicts likely benign (score 0.1001) — an in-silico prediction, not a clinical call.

SPAST p.Pro109Arg

c.326C>G · rs762722729 · VCV2164623

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1001 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0212%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary spastic paraplegia 4

Computational evidence

Protein change
AlphaMissense	0.1001	likely benign
REVEL	0.171	moderately benign-leaning
SaProt	LLR -8.07	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 2.5	GERP 0.33, phastCons 0.99
Regional constraint	o/e 1.22	unconstrained · MANE · 52 kb · p 3.5e-06 · regional, not allelic
Overall
CADD	20.5	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 0.0212% Middle Eastern · 1/4,712 alleles

Filtering AF 0.000631% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000486%

Overall 0.0009% 14/1,555,378 alleles · ultra-rare exomes 13/1,403,552 · genomes 1/151,826 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0212%	4,712
European (non-Finnish)	0.00113%	88,485

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.Pro109Arg
Coding: c.326C>G
MANE Select: NM_014946
dbSNP: rs762722729
Type: single nucleotide variant
Location: chr2:32064157 (GRCh38)
Gene constraint: LOEUF 0.69 · pLI 0.11 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.03 · 7 PDB
Residue 109: a UniProt-annotated variant site (in spg4); the 'required for interaction with rtn1' region; the 'required for midbody localization' 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.Pro109= Likely benign ★ same residue
SPAST p.Pro109Leu Likely benign ★ 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
SPAST c.1099-1G>A Pathogenic ★★ same condition
SPAST c.1099-2A>C Pathogenic/Likely 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-pro109arg (accessed [today's date]).

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