SCYL3

Chr 1

SCY1 like pseudokinase 3

Also known as: PACE-1, PACE1

NCBI Gene: 57147 ENSG00000000457 UniProt: Q8IZE3 OMIM: 608192

This gene encodes a protein with a kinase domain and HEAT repeats that regulates cell adhesion and migration by interacting with ezrin. Mutations cause autosomal recessive peripheral neuropathy with early onset in infancy or childhood. The gene shows significant constraint against loss-of-function variants (LOEUF 0.42), indicating intolerance to protein-truncating mutations.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a protein with a kinase domain and four HEAT repeats. The encoded protein interacts with the C-terminal domain of ezrin, an ERM protein, and may play a role in cell adhesion and migration. Alternative splicing results in multiple transcript variants encoding multiple isoforms. [provided by RefSeq, Jun 2012]

OMIM ResearchGenerating clinical summary…

Clinical highlights

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.42

LOEUF

Multiple*

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.42LOEUF

pLI 0.282

Z-score 4.16

OE 0.23 (0.14–0.42)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

0.98Z-score

OE missense 0.86 (0.78–0.94)

332 obs / 386.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.23 (0.14–0.42)

0≤0.351.4

Missense OE?0.86 (0.78–0.94)

0≤0.61.4

Synonymous OE?0.93

0≤1.21.6

LoF obs/exp: 8 / 34.3Missense obs/exp: 332 / 386.5Syn Z: 0.71

Background carrier burden — how many people carry a rare variant somewhere in SCYL3?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 86

851 rare PASS variants

Rare truncating (LoF)

1 in 1,000

122 rare PASS variants

Rare synonymous (reference)

1 in 110

309 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for SCYL3. 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 86	1 in 1,100
South Asian	~43k	1 in 69	1 in 400
Remaining (unassigned)	~30k	1 in 76	1 in 650
European (Finnish)	~27k	1 in 260	≈ 1 in 6,700
Admixed American	~22k	1 in 59	1 in 1,100
African / African American	~21k	1 in 63	1 in 990
East Asian	~20k	1 in 78	1 in 1,200
Ashkenazi Jewish	~13k	1 in 930	1 in 890
Middle Eastern	~2,884	1 in 69	≈ 1 in 720

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): 10 of 12 coding exons well covered in gnomAD exomes; exons 5, 8 marginal. Genomes: all 12.? see exons ↓