Is SPAST p.Val358Phe (c.1072G>T) pathogenic?

SPAST p.Val358Phe (c.1072G>T) is classified Likely pathogenic in SPAST (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-12). AlphaMissense: likely pathogenic (0.9677); Absent from gnomAD v4.1.

How common is SPAST p.Val358Phe (c.1072G>T) in the general population?

SPAST p.Val358Phe (c.1072G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SPAST p.Val358Phe (c.1072G>T)?

AlphaMissense predicts likely pathogenic (score 0.9677) — an in-silico prediction, not a clinical call.

SPAST p.Val358Phe

c.1072G>T · VCV3378020

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9677 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9677	likely pathogenic ✓ concordant with ClinVar
REVEL	0.969	strongly pathogenic-leaning
SaProt	LLR -13.23	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 0.39	unconstrained · MANE · 26 kb · p 1.7e-17 · regional, not allelic
Overall
CADD	29.6	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: SPAST
Protein: p.Val358Phe
Coding: c.1072G>T
MANE Select: NM_014946
Type: single nucleotide variant
Location: chr2:32116186 (GRCh38)
Gene constraint: LOEUF 0.69 · pLI 0.11 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.03 · 7 PDB
Residue 358: the 'sufficient for microtubule severing' region; an α-helix; a UniProt-annotated variant site (in spg4)

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

Similar variants

SPAST c.1004+1G>C Pathogenic/Likely pathogenic ★★ same type
SPAST c.1004+1G>T Pathogenic ★★ same type
SPAST c.1004+2T>G Pathogenic ★★ same type
SPAST c.1098+1G>A Pathogenic ★★ same type
SPAST c.1099-1G>A Pathogenic ★★ same type
SPAST c.1099-2A>C Pathogenic/Likely pathogenic ★★ same type
SPAST c.1173+1G>A Pathogenic/Likely pathogenic ★★ same type
SPAST c.1174-1G>A Pathogenic ★★ same type

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-val358phe (accessed [today's date]).

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