Is KIF1A p.Val504Leu (c.1510G>C) pathogenic?

KIF1A p.Val504Leu (c.1510G>C) is classified Uncertain significance in KIF1A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-06). AlphaMissense: likely pathogenic (0.9847); Very rare (popmax 0.0011%, sas); Associated with neuropathy, hereditary sensory, type 2C.

What condition is associated with KIF1A p.Val504Leu (c.1510G>C)?

KIF1A p.Val504Leu (c.1510G>C) is associated with neuropathy, hereditary sensory, type 2C, hereditary spastic paraplegia 30, intellectual disability, autosomal dominant 9 (ClinVar).

How common is KIF1A p.Val504Leu (c.1510G>C) in the general population?

KIF1A p.Val504Leu (c.1510G>C) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about KIF1A p.Val504Leu (c.1510G>C)?

AlphaMissense predicts likely pathogenic (score 0.9847) — an in-silico prediction, not a clinical call.

KIF1A p.Val504Leu

Q: How is Hereditary sensory and autonomic neuropathy type 2 inherited?

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

c.1510G>C · rs1275774750 · VCV2143849

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9847 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

neuropathy, hereditary sensory, type 2C

Computational evidence

Protein change
AlphaMissense	0.9847	likely pathogenic
REVEL	0.511	indeterminate
SaProt	LLR -7.72	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.4	GERP 2, phastCons 1
Regional constraint	o/e 0.51	unconstrained · MANE · 8,885 bp · p 2.9e-24 · regional, not allelic
Overall
CADD	25.7	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM V495L vs ClinVar V504L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,024 alleles

Filtering AF 0.0005% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000366%

Overall 0.000744% 12/1,613,424 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,024
European (non-Finnish)	0.000932%	107,246

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.Val504Leu
Coding: c.1510G>C
MANE Select: NM_001244008
dbSNP: rs1275774750
Type: single nucleotide variant
Location: chr2:240767333 (GRCh38)
Gene constraint: LOEUF 0.304 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 71.38 · 21 PDB
Residue 504: a β-strand

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

Disease context

neuropathy, hereditary sensory, type 2C — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary spastic paraplegia 30 intellectual disability, autosomal dominant 9

For Hereditary sensory and autonomic neuropathy type 2 (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

KIF1A p.Val504Ile Uncertain significance ★ ⚠ same residue
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

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-val504leu (accessed [today's date]).

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