SYTL2

Chr 11

synaptotagmin like 2

Also known as: CHR11SYT, EXO4, PPP1R151, SGA72M, SLP2, SLP2A

NCBI Gene: 54843 ENSG00000137501 UniProt: Q9HCH5 OMIM: 612880

SYTL2 encodes synaptotagmin-like protein 2, which acts as a RAB27A effector protein controlling vesicle trafficking, cytotoxic granule exocytosis in lymphocytes, and glucagon-containing granule recruitment in pancreatic alpha cells. Mutations cause autosomal recessive familial hemophagocytic lymphohistiocytosis type 5, a severe immunodeficiency disorder affecting the hematopoietic and immune systems. The gene shows high tolerance to loss-of-function variants (LOEUF 1.01), suggesting that pathogenic variants may involve specific functional disruptions rather than complete protein loss.

OMIM ResearchSummary from RefSeq, UniProt

The protein encoded by this gene is a synaptotagmin-like protein (SLP) that belongs to a C2 domain-containing protein family. The SLP homology domain (SHD) of this protein has been shown to specifically bind the GTP-bound form of Ras-related protein Rab-27A (RAB27A). This protein plays a role in RAB27A-dependent vesicle trafficking and controls melanosome distribution in the cell periphery. Alternative splicing results in multiple transcript variants encoding distinct isoforms.[provided by RefSeq, Jun 2009]

OMIM ResearchGenerating clinical summary…

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.01

LOEUF

Multiple*

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.01LOEUF

pLI 0.000

Z-score 1.49

OE 0.77 (0.59–1.01)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-1.20Z-score

OE missense 1.13 (1.07–1.21)

725 obs / 639.4 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.77 (0.59–1.01)

0≤0.351.4

Missense OE?1.13 (1.07–1.21)

0≤0.61.4

Synonymous OE?0.93

0≤1.21.6

LoF obs/exp: 38 / 49.3Missense obs/exp: 725 / 639.4Syn Z: 0.84

Background carrier burden — how many people carry a rare variant somewhere in SYTL2?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 20

3,052 rare PASS variants

Rare truncating (LoF)

1 in 180

438 rare PASS variants

Rare synonymous (reference)

1 in 46

1,033 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for SYTL2. 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 30	1 in 210
South Asian	~43k	1 in 18	1 in 180
Remaining (unassigned)	~30k	1 in 16	1 in 170
European (Finnish)	~27k	1 in 63	1 in 580
Admixed American	~22k	1 in 18	1 in 190
African / African American	~21k	1 in 16	1 in 210
East Asian	~20k	1 in 22	1 in 150
Ashkenazi Jewish	~13k	1 in 62	1 in 420
Middle Eastern	~2,884	1 in 19	1 in 170

Each group is summed over the variants that are rare in that group. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 17 of 19 coding exons well covered in gnomAD exomes; exons 6, 15 marginal. Genomes: all 19.? see exons ↓