Is SPAST p.Arg7Pro (c.20G>C) pathogenic?

SPAST p.Arg7Pro (c.20G>C) is classified Uncertain significance in SPAST (ClinVar, Single submitter, 1 submitter; last evaluated 2021-12-02). AlphaMissense: likely pathogenic (0.7099); Very rare (popmax 0.000513%, nfe); Associated with hereditary spastic paraplegia 4.

What condition is associated with SPAST p.Arg7Pro (c.20G>C)?

SPAST p.Arg7Pro (c.20G>C) is associated with hereditary spastic paraplegia 4 (ClinVar).

How common is SPAST p.Arg7Pro (c.20G>C) in the general population?

SPAST p.Arg7Pro (c.20G>C) is very rare (popmax 0.000513%, nfe) (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.Arg7Pro (c.20G>C)?

AlphaMissense predicts likely pathogenic (score 0.7099) — an in-silico prediction, not a clinical call.

SPAST p.Arg7Pro

c.20G>C · rs750900931 · VCV1384983

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7099 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000513%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

hereditary spastic paraplegia 4

Computational evidence

Protein change
AlphaMissense	0.7099	likely pathogenic
REVEL	0.564	indeterminate
SaProt	LLR -7.20	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 2, phastCons 1
Regional constraint	o/e 1.22	unconstrained · MANE · 52 kb · p 3.5e-06 · regional, not allelic
Overall
CADD	26.8	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

Grpmax group 0.000513% European (non-Finnish) · 6/1,170,482 alleles

Filtering AF 0.000184% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000121%

Overall 0.000379% 6/1,581,606 alleles · very rare exomes 4/1,429,578 · genomes 2/152,028 · 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.Arg7Pro
Coding: c.20G>C
MANE Select: NM_014946
dbSNP: rs750900931
Type: single nucleotide variant
Location: chr2:32063851 (GRCh38)
Gene constraint: LOEUF 0.69 · pLI 0.11 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.03 · 7 PDB
Residue 7: 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.Arg7Ter Pathogenic ★ same residue
SPAST p.Arg7= Conflicting classifications of pathogenicity ★ same residue
SPAST p.Arg7Leu 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
SPAST c.1099-1G>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-arg7pro (accessed [today's date]).

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