Is SPAST p.Ser103Pro (c.307T>C) pathogenic?

SPAST p.Ser103Pro (c.307T>C) is classified Conflicting classifications of pathogenicity in SPAST (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-06-27). AlphaMissense: likely benign (0.0595); Very rare (popmax 0.00949%, afr); Associated with Inborn genetic diseases.

What condition is associated with SPAST p.Ser103Pro (c.307T>C)?

SPAST p.Ser103Pro (c.307T>C) is associated with Inborn genetic diseases, hereditary spastic paraplegia 4 (ClinVar).

How common is SPAST p.Ser103Pro (c.307T>C) in the general population?

SPAST p.Ser103Pro (c.307T>C) is very rare (popmax 0.00949%, afr) (gnomAD).

What do computational predictors say about SPAST p.Ser103Pro (c.307T>C)?

AlphaMissense predicts likely benign (score 0.0595) — an in-silico prediction, not a clinical call.

SPAST p.Ser103Pro

c.307T>C · VCV3960326

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0595 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00949%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0595	likely benign
REVEL	0.314	indeterminate
SaProt	LLR -4.17	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.5	GERP -0.22, phastCons 1
Regional constraint	o/e 1.22	unconstrained · MANE · 52 kb · p 3.5e-06 · regional, not allelic
Overall
CADD	19.27	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 0.00949% African / African-American · 7/73,724 alleles

Filtering AF 0.00444% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00313%

Overall 0.000446% 7/1,570,320 alleles · very rare exomes 1/1,418,398 · genomes 6/151,922 · joint denominator

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.Ser103Pro
Coding: c.307T>C
MANE Select: NM_014946
Type: single nucleotide variant
Location: chr2:32064138 (GRCh38)
Gene constraint: LOEUF 0.69 · pLI 0.11 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.03 · 7 PDB
Residue 103: a UniProt-annotated variant site (in spg4); the 'required for interaction with rtn1' region; the 'required for midbody localization' 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

Also linked: hereditary spastic paraplegia 4

Similar variants

SPAST p.Ser103Ala 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-ser103pro (accessed [today's date]).

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