Is SPAST p.Pro42= (c.126C>G) pathogenic?

SPAST p.Pro42= (c.126C>G) is classified Likely benign in SPAST (ClinVar, Single submitter, 1 submitter; last evaluated 2018-11-27). Very rare (popmax 0.00535%, afr); Associated with hereditary spastic paraplegia 4.

What condition is associated with SPAST p.Pro42= (c.126C>G)?

SPAST p.Pro42= (c.126C>G) is associated with hereditary spastic paraplegia 4 (ClinVar).

How common is SPAST p.Pro42= (c.126C>G) in the general population?

SPAST p.Pro42= (c.126C>G) is very rare (popmax 0.00535%, 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.

SPAST p.Pro42=

c.126C>G · rs755151658 · VCV744691

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00535%, afr)

Conditions

hereditary spastic paraplegia 4

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.3	GERP -3.6
Overall
CADD	4.18	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00535% African / African-American · 4/74,822 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.000683% 11/1,611,636 alleles · very rare exomes 8/1,459,454 · genomes 3/152,182 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00535%	18,706
Admixed American	0.00334%	29,914
South Asian	0.0033%	30,259
Remaining individualsnot grpmax-eligible	0.0016%	62,340
European (non-Finnish)	8.48e-05%	1,178,887

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.Pro42=
Coding: c.126C>G
MANE Select: NM_014946
dbSNP: rs755151658
Type: single nucleotide variant
Location: chr2:32063957 (GRCh38)
Gene constraint: LOEUF 0.69 · pLI 0.11 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.03 · 7 PDB
Residue 42: 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.Pro42Ala Uncertain significance ★ ⚠ same residue
SPAST p.Pro42Thr 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
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-pro42 (accessed [today's date]).

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