Is SPAST p.Pro22Ser (c.64C>T) pathogenic?

SPAST p.Pro22Ser (c.64C>T) is classified Likely benign in SPAST (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-20). AlphaMissense: likely benign (0.0727); Ultra-rare (popmax 0.0432%, sas); Associated with Inborn genetic diseases.

What condition is associated with SPAST p.Pro22Ser (c.64C>T)?

SPAST p.Pro22Ser (c.64C>T) is associated with Inborn genetic diseases (ClinVar).

How common is SPAST p.Pro22Ser (c.64C>T) in the general population?

SPAST p.Pro22Ser (c.64C>T) is ultra-rare (popmax 0.0432%, sas) (gnomAD).

What do computational predictors say about SPAST p.Pro22Ser (c.64C>T)?

AlphaMissense predicts likely benign (score 0.0727) — an in-silico prediction, not a clinical call.

SPAST p.Pro22Ser

c.64C>T · VCV3321838

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0727 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0432%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0727	likely benign
REVEL	0.228	benign-leaning
SaProt	LLR -8.47	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.4	GERP 0.16, phastCons 1
Regional constraint	o/e 1.22	unconstrained · MANE · 52 kb · p 3.5e-06 · regional, not allelic
Overall
CADD	19.19	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 0.0432% South Asian · 38/87,924 alleles

Filtering AF 0.0323% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0285%

Overall 0.00247% 39/1,581,732 alleles · ultra-rare exomes 39/1,429,646 · genomes 0/152,086 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0432%	2,314
European (non-Finnish)	8.58e-05%	1,166,077

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.Pro22Ser
Coding: c.64C>T
MANE Select: NM_014946
Type: single nucleotide variant
Location: chr2:32063895 (GRCh38)
Gene constraint: LOEUF 0.69 · pLI 0.11 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.03 · 7 PDB
Residue 22: 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

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

Similar variants

SPAST p.Pro22Ala Likely benign ★★ same residue
SPAST p.Pro22His Uncertain significance ★ ⚠ same residue
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

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-pro22ser (accessed [today's date]).

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