Is SPAST p.Lys10= (c.30G>A) pathogenic?

SPAST p.Lys10= (c.30G>A) is classified Conflicting classifications of pathogenicity in SPAST (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-07-20). Very rare (popmax 0.00751%, nfe); Associated with hereditary spastic paraplegia 4.

What condition is associated with SPAST p.Lys10= (c.30G>A)?

SPAST p.Lys10= (c.30G>A) is associated with hereditary spastic paraplegia 4, hereditary spastic paraplegia (ClinVar).

How common is SPAST p.Lys10= (c.30G>A) in the general population?

SPAST p.Lys10= (c.30G>A) is very rare (popmax 0.00751%, 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.

SPAST p.Lys10=

c.30G>A · rs768928614 · VCV897736

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00751%, nfe)

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 7.7	GERP 1.1, phastCons 1
Overall
CADD	13.31	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00751% European (non-Finnish) · 88/1,171,036 alleles

Filtering AF 0.00619% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00577%

Overall 0.00574% 91/1,584,890 alleles · very rare exomes 84/1,432,778 · genomes 7/152,112 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00751%	13,307
Admixed American	0.00178%	56,024
Remaining individualsnot grpmax-eligible	0.00163%	61,486
African / African-American	0.00134%	74,574

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.Lys10=
Coding: c.30G>A
MANE Select: NM_014946
dbSNP: rs768928614
Type: single nucleotide variant
Location: chr2:32063861 (GRCh38)
Gene constraint: LOEUF 0.69 · pLI 0.11 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.03 · 7 PDB
Residue 10: 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

Also linked: hereditary spastic paraplegia

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.Lys10Asn Uncertain significance ★ ⚠ same residue
SPAST p.Lys10Gln Uncertain significance ★ same residue
SPAST p.Lys10Arg 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-lys10 (accessed [today's date]).

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