Is SPAST p.Phe53Val (c.157T>G) pathogenic?

SPAST p.Phe53Val (c.157T>G) is classified Conflicting classifications of pathogenicity in SPAST (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-12-01). AlphaMissense: likely benign (0.1498); Ultra-rare (popmax 0.012%, afr); Associated with hereditary spastic paraplegia 4.

What condition is associated with SPAST p.Phe53Val (c.157T>G)?

SPAST p.Phe53Val (c.157T>G) is associated with hereditary spastic paraplegia 4 (ClinVar).

How common is SPAST p.Phe53Val (c.157T>G) in the general population?

SPAST p.Phe53Val (c.157T>G) is ultra-rare (popmax 0.012%, 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.

What do computational predictors say about SPAST p.Phe53Val (c.157T>G)?

AlphaMissense predicts likely benign (score 0.1498) — an in-silico prediction, not a clinical call.

SPAST p.Phe53Val

c.157T>G · rs200029938 · VCV963046

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1498 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.012%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

hereditary spastic paraplegia 4

Computational evidence

Protein change
AlphaMissense	0.1498	likely benign
REVEL	0.494	indeterminate
SaProt	LLR -5.52	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.6	GERP 1.8, phastCons 1
Regional constraint	o/e 1.22	unconstrained · MANE · 52 kb · p 3.5e-06 · regional, not allelic
Overall
CADD	22.2	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 0.012% African / African-American · 9/75,002 alleles

Filtering AF 0.00623% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00467%

Overall 0.00242% 39/1,613,398 alleles · ultra-rare exomes 34/1,461,170 · genomes 5/152,228 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.012%	8,334
European (non-Finnish)	0.00246%	40,674
Remaining individualsnot grpmax-eligible	0.0016%	62,458

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.Phe53Val
Coding: c.157T>G
MANE Select: NM_014946
dbSNP: rs200029938
Type: single nucleotide variant
Location: chr2:32063988 (GRCh38)
Gene constraint: LOEUF 0.69 · pLI 0.11 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.03 · 7 PDB
Residue 53: the 'required for interaction with ssna1 and microtubules' region; a UniProt-annotated variant site (in spg4); the 'required for interaction with rtn1' region; the 'required for midbody localization' region; the 'required for interaction with atl1' 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.Phe53Leu 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
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-phe53val (accessed [today's date]).

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