KIDINS220

Chr 2ADAR

kinase D interacting substrate 220

Also known as: ARMS, SINO, VENARG

NCBI Gene: 57498 ENSG00000134313 UniProt: Q9ULH0 OMIM: 615759

This gene encodes a transmembrane scaffold protein that controls neuronal survival, differentiation, and synaptic plasticity by mediating crosstalk between neurotrophin signaling and other intracellular pathways, including sustained ERK activation through Rap1-dependent mechanisms. Mutations cause a neurodevelopmental syndrome characterized by spastic paraplegia, intellectual disability, nystagmus, and obesity, as well as ventriculomegaly and arthrogryposis, with both autosomal dominant and autosomal recessive inheritance patterns reported.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a transmembrane protein that is preferentially expressed in the nervous system where it controls neuronal cell survival, differentiation into exons and dendrites, and synaptic plasticity. The encoded protein interacts with membrane receptors, cytosolic signaling components, and cytoskeletal proteins, serving as a scaffold that mediates crosstalk between the neurotrophin pathway and several other intracellular signaling pathways. Aberrant expression of this gene is associated with the onset of various neuropsychiatric disorders and neurodegenerative diseases, including Alzheimer's disease. Naturally occurring mutations in this gene are associated with a syndrome characterized by spastic paraplegia, intellectual disability, nystagmus and obesity. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2017]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Spastic paraplegia, intellectual disability, nystagmus, and obesityMIM #617296

Ventriculomegaly and arthrogryposisMIM #619501

Clinical highlights

Gene–disease validity (ClinGen)

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype) and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.35

LOEUF

LOF

Mechanism· G2P

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.35LOEUF

pLI 0.074

Z-score 6.41

OE 0.24 (0.17–0.35)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

2.26Z-score

OE missense 0.80 (0.75–0.84)

780 obs / 979.1 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.24 (0.17–0.35)

0≤0.351.4

Missense OE?0.80 (0.75–0.84)

0≤0.61.4

Synonymous OE?0.99

0≤1.21.6

LoF obs/exp: 20 / 83.0Missense obs/exp: 780 / 979.1Syn Z: 0.22

Background carrier burden — how many people carry a rare variant somewhere in KIDINS220?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 32

1,991 rare PASS variants

Rare truncating (LoF)

1 in 700

175 rare PASS variants

Rare synonymous (reference)

1 in 49

800 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for KIDINS220. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 39	1 in 850
South Asian	~43k	1 in 24	1 in 300
Remaining (unassigned)	~30k	1 in 29	1 in 790
European (Finnish)	~27k	1 in 190	1 in 2,000
Admixed American	~22k	1 in 35	1 in 350
African / African American	~21k	1 in 31	1 in 1,700
East Asian	~20k	1 in 36	1 in 800
Ashkenazi Jewish	~13k	1 in 220	1 in 2,300
Middle Eastern	~2,884	1 in 26	≈ 1 in 1,400

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 20 of 29 coding exons well covered in gnomAD exomes; exons 2, 3, 4, 5, 6 and 4 more marginal. Genomes: all 29.? see exons ↓