SDK1

Chr 7

sidekick cell adhesion molecule 1

NCBI Gene: 221935 ENSG00000146555 OMIM: 607216

This adhesion molecule promotes lamina-specific synaptic connections in the retina through homophilic interactions and is expressed in specific subsets of interneurons and retinal ganglion cells. Mutations cause autosomal recessive retinal dystrophy and microcephaly. The gene is highly constrained against loss-of-function variants, indicating that complete loss of protein function is poorly tolerated.

OMIM ResearchSummary from RefSeq, UniProt

The protein encoded by this gene is a member of the immunoglobulin superfamily. The protein contains six immunoglobulin-like domains and thirteen fibronectin type III domains. Fibronectin type III domains are present in both extracellular and intracellular proteins and tandem repeats are known to contain binding sites for DNA, heparin and the cell surface. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2016]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.40

Clinical Summary— SDK1

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.29) despite low pLI — interpret in context.

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ClinVar Variants

479 VUS of 600 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.40LOEUF

pLI 0.000

Z-score 6.70

OE 0.29 (0.22–0.40)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

-2.10Z-score

OE missense 1.16 (1.11–1.21)

1558 obs / 1341.5 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.29 (0.22–0.40)

0≤0.351.4

Missense OE?1.16 (1.11–1.21)

0≤0.61.4

Synonymous OE?1.34

0≤1.21.6

LoF obs/exp: 31 / 105.1Missense obs/exp: 1558 / 1341.5Syn Z: -6.61

This gene — mechanism propensity

0.7035th %ile

GOF

0.6638th %ile

LOF

0.3841th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median

GOFprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

600 submitted variants in ClinVar

ClinVar

Classification Summary

VUS479

Likely Benign41

Benign16

479

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0
Likely Pathogenic	0	0	0	0
VUS	476	2	1	479
Likely Benign	23	2	16	41
Benign	6	1	9	16
Total	505	5	26	536

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

View in ClinVar →

37 pathogenic / likely-pathogenic (of 78) ClinVar copy-number / structural variants overlap SDK1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →