chr2-240722507-GCG-ACA

Variant names:

• chr2-240722507-GCG-ACA
• NM_001244008.2:c.4612_4614delCGCinsTGT
• KIF1A p.Arg1538Cys

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+2 Uncertain · Warm

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 2 classification points (ACGS-UK Somatic Oncogenicity v2025). O3_Moderate

The NM_001244008.2(KIF1A):c.4612_4614delCGCinsTGT (p.Arg1538Cys) variant causes a missense change. Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.R1538C: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 464253); p.R1538H: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 1355067) This exact variant is curated in the UniProt human variants database as Uncertain Significance; it is also listed as a COSMIC curated somatic variant.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KIF1A NM_001244008.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.67
• Publications: 0 publications found

Genes affected

KIF1A (HGNC:888): (kinesin family member 1A) The protein encoded by this gene is a member of the kinesin family and functions as an anterograde motor protein that transports membranous organelles along axonal microtubules. Mutations at this locus have been associated with spastic paraplegia-30 and hereditary sensory neuropathy IIC. Alternatively spliced transcript variants encoding distinct isoforms have been described. [provided by RefSeq, Apr 2012]

KIF1A Gene-Disease associations (from GenCC):

• intellectual disability, autosomal dominant 9

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P
• syndromic intellectual disability

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• neuropathy, hereditary sensory, type 2C

  Inheritance: AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: PanelApp Australia, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• hereditary spastic paraplegia 30

  Inheritance: AD, AR Classification: STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet
• spastic paraplegia 30A, autosomal dominant

  Inheritance: AD, AR Classification: STRONG Submitted by: PanelApp Australia
• autosomal dominant non-syndromic intellectual disability

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• PEHO syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary sensory and autonomic neuropathy type 2

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

Classification according to ACGS-UK Somatic Oncogenicity v2025

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 2 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	O3Absent or very rare in population		Absent or extremely rare in gnomAD (AC ≤ 2) — O3 moderate; GnomAD: AF = absent, AC = 0 — absent/extremely rare (O3 moderate [+2])

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_001244008.2. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	KIF1A NM_001244008.2	MANE Select	c.4612_4614delCGCinsTGT p.Arg1538Cys	missense	N/A	Prot: NP_001230937.1 UniProt:
	KIF1A NM_001379631.1		c.4687_4689delCGCinsTGT p.Arg1563Cys	missense	N/A	Prot: NP_001366560.1
	KIF1A NM_001379642.1		c.4612_4614delCGCinsTGT p.Arg1538Cys	missense	N/A	Prot: NP_001366571.1

KIF1A NM_001244008.2

MANE Select

HGVSc / HGVSpc.4612_4614delCGCinsTGTp.Arg1538Cys

Exon rankN/A

missense

Prot: NP_001230937.1UniProt: Q12756-3

KIF1A NM_001379631.1

HGVSc / HGVSpc.4687_4689delCGCinsTGTp.Arg1563Cys

Exon rankN/A

missense

Prot: NP_001366560.1

KIF1A NM_001379642.1

HGVSc / HGVSpc.4612_4614delCGCinsTGTp.Arg1538Cys

Exon rankN/A

missense

Prot: NP_001366571.1

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	KIF1A ENST00000498729.9	TSL:5MANE Select	c.4612_4614delCGCinsTGT p.Arg1538Cys	missense	N/A	Prot: ENSP00000438388.1 UniProt:
	KIF1A ENST00000460788.5	TSL:1	n.1169_1171delCGCinsTGT	non_coding_transcript_exon	Exon 3 of 9	Prot:
	KIF1A ENST00000492812.6	TSL:1	n.3195_3197delCGCinsTGT	non_coding_transcript_exon	Exon 10 of 16	Prot:

KIF1A ENST00000498729.9

TSL:5MANE Select

HGVSc / HGVSpc.4612_4614delCGCinsTGTp.Arg1538Cys

Exon rankN/A

missense

Prot: ENSP00000438388.1UniProt: Q12756-3

KIF1A ENST00000460788.5

TSL:1

HGVSc / HGVSpn.1169_1171delCGCinsTGT

Exon rankExon 3 of 9

non_coding_transcript_exon

Prot:

KIF1A ENST00000492812.6

TSL:1

HGVSc / HGVSpn.3195_3197delCGCinsTGT

Exon rankExon 10 of 16

non_coding_transcript_exon

Prot:

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 2 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:33
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:33

Showing 2 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
PhyloP100	Benign	1.7

Showing 1 of 1 scores

Splicing Scores

No splicing scores have been computed for this variant.

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

hg19: chr2-241661924;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar