SCYL2

Chr 12AR

SCY1 like pseudokinase 2

Also known as: AMC4, AMCNACC, CVAK104

NCBI Gene: 55681 ENSG00000136021 UniProt: Q6P3W7 OMIM: 616365

The protein functions as a component of clathrin-coated complexes, regulating clathrin-dependent trafficking between the plasma membrane, trans-Golgi network, and endosomal system, and plays an essential role in neuronal function by regulating excitatory receptor expression at synapses. Biallelic mutations cause arthrogryposis multiplex congenita 4, neurogenic, with agenesis of the corpus callosum, inherited in an autosomal recessive pattern. The gene shows moderate constraint against loss-of-function variants (LOEUF 0.42), consistent with its role in essential cellular trafficking processes.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene associates with clathrin-coated complexes at the plasma membrane and with endocytic coated vesicles. The encoded protein phosphorylates the beta2 subunit of the plasma membrane adapter complex AP2 and interacts with clathrin, showing involvement in clathrin-dependent pathways between the trans-Golgi network and the endosomal system. In addition, this protein has a role in the Wnt signaling pathway by targeting frizzled 5 (Fzd5) for lysosomal degradation. Two transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Dec 2015]

OMIM ResearchGenerating clinical summary…

ARLOEUF 0.421 OMIM phenotype

Clinical Summary— SCYL2

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.25) despite low pLI — interpret in context.

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ClinVar Variants

9 unique Pathogenic / Likely Pathogenic· 114 VUS of 159 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?

0.42LOEUF

pLI 0.077

Z-score 4.56

OE 0.25 (0.16–0.42)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.25Z-score

OE missense 0.84 (0.77–0.91)

389 obs / 464.9 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.25 (0.16–0.42)

0≤0.351.4

Missense OE?0.84 (0.77–0.91)

0≤0.61.4

Synonymous OE?0.96

0≤1.21.6

LoF obs/exp: 11 / 43.4Missense obs/exp: 389 / 464.9Syn Z: 0.39

ClinVar Variant Classifications

159 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic4

Likely Pathogenic5

VUS114

Likely Benign10

Benign4

Pathogenic

Likely Pathogenic

114

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	3	1	0	0	4
Likely Pathogenic	5	0	0	0	5
VUS	2	110	2	0	114
Likely Benign	0	5	2	3	10
Benign	0	1	2	1	4
Total	10	117	6	4	137

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

View in ClinVar →

9 pathogenic / likely-pathogenic (of 17) ClinVar copy-number / structural variants overlap SCYL2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →