Is KIF1A p.Ser992= (c.2976A>G) pathogenic?

KIF1A p.Ser992= (c.2976A>G) is classified Uncertain significance in KIF1A (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-07-08). Very rare (popmax 0.00051%, nfe); Associated with hereditary spastic paraplegia 30.

What condition is associated with KIF1A p.Ser992= (c.2976A>G)?

KIF1A p.Ser992= (c.2976A>G) is associated with hereditary spastic paraplegia 30, neuropathy, hereditary sensory, type 2C, intellectual disability, autosomal dominant 9 (ClinVar).

How common is KIF1A p.Ser992= (c.2976A>G) in the general population?

KIF1A p.Ser992= (c.2976A>G) is very rare (popmax 0.00051%, nfe) (gnomAD).

How is Autosomal spastic paraplegia type 30 inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

KIF1A p.Ser992=

c.2976A>G · rs2049077964 · VCV852799

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00051%, nfe)

Conditions

hereditary spastic paraplegia 30

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.1	GERP 1.3, phastCons 1
Overall
CADD	19.66	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00051% European (non-Finnish) · 6/1,176,764 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000121%

Overall 0.000373% 6/1,610,178 alleles · very rare exomes 4/1,457,932 · genomes 2/152,246 · 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: KIF1A
Protein: p.Ser992=
Coding: c.2976A>G
MANE Select: NM_001244008
dbSNP: rs2049077964
Type: single nucleotide variant
Location: chr2:240750430 (GRCh38)
Gene constraint: LOEUF 0.304 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 71.38 · 21 PDB
Residue 992: a UniProt-annotated variant site (in spg30a)

Full KIF1A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hereditary spastic paraplegia 30 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: neuropathy, hereditary sensory, type 2C intellectual disability, autosomal dominant 9

For Autosomal spastic paraplegia type 30 (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Adolescent, Adult

Similar variants

KIF1A c.2582+1G>A Pathogenic/Likely pathogenic ★★ same condition
KIF1A c.798+1G>A Pathogenic/Likely pathogenic ★★ same condition
KIF1A p.Ala255Asp Likely pathogenic ★★ same condition
KIF1A p.Ala85Asp Pathogenic/Likely pathogenic ★★ same condition
KIF1A p.Arg11Gln Pathogenic/Likely pathogenic ★★ same condition
KIF1A p.Arg11Trp Pathogenic/Likely pathogenic ★★ same condition
KIF1A p.Arg13Cys Pathogenic/Likely pathogenic ★★ same condition
KIF1A p.Arg13His 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/kif1a-p-ser992 (accessed [today's date]).

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