Is SPAST p.Phe368Ser (c.1103T>C) pathogenic?

SPAST p.Phe368Ser (c.1103T>C) is classified Pathogenic/Likely pathogenic in SPAST (ClinVar, Multiple submitters, 3 submitters; last evaluated 2022-07-27). AlphaMissense: likely pathogenic (0.9993); Absent from gnomAD v4.1; Associated with SPAST-related disorder.

What condition is associated with SPAST p.Phe368Ser (c.1103T>C)?

SPAST p.Phe368Ser (c.1103T>C) is associated with SPAST-related disorder, hereditary spastic paraplegia 4 (ClinVar).

How common is SPAST p.Phe368Ser (c.1103T>C) in the general population?

SPAST p.Phe368Ser (c.1103T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SPAST p.Phe368Ser (c.1103T>C)?

AlphaMissense predicts likely pathogenic (score 0.9993) — an in-silico prediction, not a clinical call.

SPAST p.Phe368Ser

c.1103T>C · rs1553316799 · VCV536436

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9993 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

SPAST-related disorder

Computational evidence

Protein change
AlphaMissense	0.9993	likely pathogenic ✓ concordant with ClinVar · top 1% in SPAST
REVEL	0.966	strongly pathogenic-leaning
SaProt	LLR -13.78	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>G here scores Δ0.31 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.8	GERP 1.9, phastCons 1
Regional constraint	o/e 0.39	unconstrained · MANE · 26 kb · p 1.7e-17 · regional, not allelic
Overall
CADD	31.0	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.Phe368Ser
Coding: c.1103T>C
MANE Select: NM_014946
dbSNP: rs1553316799
Type: single nucleotide variant
Location: chr2:32126952 (GRCh38)
Gene constraint: LOEUF 0.69 · pLI 0.11 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.03 · 7 PDB
Residue 368: the 'sufficient for microtubule severing' region; a UniProt-annotated variant site (in spg4); a UniProt-annotated variant site (in spg4; uncertain significance)

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

Disease context

SPAST-related disorder

Also linked: hereditary spastic paraplegia 4

Similar variants

SPAST p.Phe368Leu Pathogenic ★ 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
SPAST c.1173+1G>A 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-phe368ser (accessed [today's date]).

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