Is KIF1B p.Val593Asp (c.1778T>A) pathogenic?

KIF1B p.Val593Asp (c.1778T>A) is classified Uncertain significance in KIF1B (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-04-08). AlphaMissense: likely pathogenic (0.8347); Absent from gnomAD v4.1; Associated with Charcot-Marie-Tooth disease type 2.

What condition is associated with KIF1B p.Val593Asp (c.1778T>A)?

KIF1B p.Val593Asp (c.1778T>A) is associated with Charcot-Marie-Tooth disease type 2 (ClinVar).

How common is KIF1B p.Val593Asp (c.1778T>A) in the general population?

KIF1B p.Val593Asp (c.1778T>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about KIF1B p.Val593Asp (c.1778T>A)?

AlphaMissense predicts likely pathogenic (score 0.8347) — an in-silico prediction, not a clinical call.

KIF1B p.Val593Asp

c.1778T>A · rs1462866416 · VCV838720

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8347 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Charcot-Marie-Tooth disease type 2

Computational evidence

Protein change
AlphaMissense	0.8347	likely pathogenic
REVEL	0.583	indeterminate
SaProt	LLR -12.24	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.1	GERP 1.3, phastCons 1
Regional constraint	o/e 1.54	unconstrained · MANE · 872 bp · p 0.0039 · regional, not allelic
Overall
CADD	26.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: KIF1B
Protein: p.Val593Asp
Coding: c.1778T>A
MANE Select: NM_001365951
dbSNP: rs1462866416
Type: single nucleotide variant
Location: chr1:10296582 (GRCh38)
Gene constraint: LOEUF 0.376 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 66.64 · 1 PDB
Residue 593: the fha domain; a β-strand

Full KIF1B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Charcot-Marie-Tooth disease type 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

KIF1B p.Val593Leu Uncertain significance ★ ⚠ same residue
KIF1B p.Val593= Likely benign ★ same residue
KIF1B c.1590+5G>A Uncertain significance ★★ same condition
KIF1B c.1671-3C>A Uncertain significance ★★ same condition
KIF1B c.1671-3C>G Uncertain significance ★★ same condition
KIF1B c.1861+3G>A Uncertain significance ★★ same condition
KIF1B c.2115+6A>T Uncertain significance ★★ same condition
KIF1B c.2358+1G>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/kif1b-p-val593asp (accessed [today's date]).

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