KNDC1

Chr 10

kinase non-catalytic C-lobe domain containing 1

Also known as: C10orf23, RASGEF2, Very-KIND, bB439H18.3, v-KIND

NCBI Gene: 85442 ENSG00000171798 UniProt: Q76NI1 OMIM: 616237

The protein is a Ras guanine nucleotide exchange factor that negatively regulates dendritic growth in neurons and may be involved in cellular senescence. Mutations cause autosomal recessive spastic paraplegia, intellectual disability, nystagmus, and obesity (SPINOBY syndrome), typically presenting in early childhood. The gene is highly constrained against loss-of-function variants (LOEUF 0.398), suggesting intolerance to protein disruption.

OMIM ResearchSummary from RefSeq, UniProt

The protein encoded by this gene is a Ras guanine nucleotide exchange factor that appears to negatively regulate dendritic growth in the brain. Knockdown of this gene in senescent umbilical vein endothelial cells partially reversed the senescence, showing that this gene could potentially be targeted by anti-aging therapies. [provided by RefSeq, Dec 2016]

OMIM ResearchGenerating clinical summary…

LOEUF 0.40

Clinical Summary— KNDC1

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.27) despite low pLI — interpret in context.

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ClinVar Variants

322 VUS of 382 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.40LOEUF

pLI 0.002

Z-score 5.76

OE 0.27 (0.19–0.40)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

0.89Z-score

OE missense 0.92 (0.87–0.97)

968 obs / 1049.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.27 (0.19–0.40)

0≤0.351.4

Missense OE?0.92 (0.87–0.97)

0≤0.61.4

Synonymous OE?1.00

0≤1.21.6

LoF obs/exp: 20 / 73.1Missense obs/exp: 968 / 1049.5Syn Z: -0.07

ClinVar Variant Classifications

382 submitted variants in ClinVar

ClinVar

Classification Summary

VUS322

Likely Benign34

Benign8

Conflicting1

322

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0	0
Likely Pathogenic	0	0	0	0	0
VUS	1	320	1	0	322
Likely Benign	0	29	0	5	34
Benign	0	6	0	2	8
Conflicting	—				1
Total	1	355	1	7	365

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

99 pathogenic / likely-pathogenic (of 119) ClinVar copy-number / structural variants overlap KNDC1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →