Is KIF1C p.Pro425= (c.1275G>A) pathogenic?

KIF1C p.Pro425= (c.1275G>A) is classified Benign/Likely benign in KIF1C (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-08-17). Rare (popmax 0.583%, sas); Associated with spastic ataxia 2.

What condition is associated with KIF1C p.Pro425= (c.1275G>A)?

KIF1C p.Pro425= (c.1275G>A) is associated with spastic ataxia 2 (ClinVar).

How common is KIF1C p.Pro425= (c.1275G>A) in the general population?

KIF1C p.Pro425= (c.1275G>A) is rare (popmax 0.583%, sas) (gnomAD).

How is Autosomal spastic paraplegia type 58 inherited?

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

KIF1C p.Pro425=

c.1275G>A · rs539482350 · VCV1985032

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

rare (popmax 0.583%, sas)

Conditions

spastic ataxia 2

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 -3.5	GERP -3.1
Overall
CADD	0.616	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.583% South Asian · 528/90,534 alleles

Filtering AF 0.542% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.526%

Overall 0.0408% 656/1,609,352 alleles · rare exomes 613/1,457,112 · genomes 43/152,240 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.583%	171
Remaining individualsnot grpmax-eligible	0.0417%	2,395
Middle Eastern	0.0331%	3,017
Ashkenazi Jewishnot grpmax-eligible	0.0102%	9,812
African / African-American	0.00806%	12,413
European (non-Finnish)	0.00755%	13,244
Admixed American	0.00172%	58,216
Finnishnot grpmax-eligible	0.00156%	63,976

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: KIF1C
Protein: p.Pro425=
Coding: c.1275G>A
MANE Select: NM_006612
dbSNP: rs539482350
Type: single nucleotide variant
Location: chr17:5007024 (GRCh38)
Gene constraint: LOEUF 0.609 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 68.43 · 2 PDB
Residue 425: the 'disordered' region

Full KIF1C gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

spastic ataxia 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Autosomal spastic paraplegia type 58 (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Adolescent, Adult, Childhood, Elderly, Infancy

Similar variants

KIF1C p.Pro425Leu Likely benign ★ same residue
KIF1C p.Arg216Cys Likely pathogenic ★★ same condition
KIF1C p.Arg669Ter Pathogenic/Likely pathogenic ★★ same condition
KIF1C p.Arg731Ter Pathogenic ★★ same condition
KIF1C p.Pro176Leu Pathogenic/Likely pathogenic ★★ same condition
KIF1C c.1415+8G>T Uncertain significance ★★ same condition
KIF1C c.1937+5G>A Uncertain significance ★★ same condition
KIF1C c.363+5G>A 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/kif1c-p-pro425 (accessed [today's date]).

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