Is SPAST p.Val596Ile (c.1786G>A) pathogenic?

SPAST p.Val596Ile (c.1786G>A) is classified Uncertain significance in SPAST (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-02-05). AlphaMissense: likely benign (0.1585); Very rare (popmax 0.00329%, sas); Associated with Inborn genetic diseases.

What condition is associated with SPAST p.Val596Ile (c.1786G>A)?

SPAST p.Val596Ile (c.1786G>A) is associated with Inborn genetic diseases (ClinVar).

How common is SPAST p.Val596Ile (c.1786G>A) in the general population?

SPAST p.Val596Ile (c.1786G>A) is very rare (popmax 0.00329%, sas) (gnomAD).

What do computational predictors say about SPAST p.Val596Ile (c.1786G>A)?

AlphaMissense predicts likely benign (score 0.1585) — an in-silico prediction, not a clinical call.

SPAST p.Val596Ile

c.1786G>A · rs1412403865 · VCV3252286

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1585 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00329%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1585	likely benign
REVEL	0.539	indeterminate
SaProt	LLR -10.57	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.75	unconstrained · MANE · 13 kb · p 0.0051 · regional, not allelic
Overall
CADD	25.3	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 0.00329% South Asian · 3/91,062 alleles

Filtering AF 0.000875% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.000744% 12/1,612,608 alleles · very rare exomes 11/1,460,512 · genomes 1/152,096 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00329%	30,354
Admixed American	0.00167%	59,986
African / African-American	0.00134%	74,876
European (non-Finnish)	0.000594%	168,410

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.Val596Ile
Coding: c.1786G>A
MANE Select: NM_014946
dbSNP: rs1412403865
Type: single nucleotide variant
Location: chr2:32154431 (GRCh38)
Gene constraint: LOEUF 0.69 · pLI 0.11 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.03 · 7 PDB
Residue 596: a UniProt-annotated variant site (in spg4); the 'sufficient for microtubule severing' region

Full SPAST gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SPAST p.Asn487Asp Likely pathogenic ★★ same condition
SPAST p.Glu356Lys Pathogenic/Likely pathogenic ★★ same condition
SPAST p.Met390Val Pathogenic ★★ ⚠ same condition
SPAST p.Ala394Val Uncertain significance ★★ ⚠ same condition
SPAST p.Ala39Asp Uncertain significance ★★ ⚠ same condition
SPAST p.Cys220Trp Uncertain significance ★★ ⚠ same condition
SPAST p.Glu602Ala Uncertain significance ★★ ⚠ same condition
SPAST p.Gly346Asp Uncertain significance ★★ ⚠ 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-val596ile (accessed [today's date]).

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