SIT1

Chr 9

signaling threshold regulating transmembrane adaptor 1

Also known as: SIT, SIT-R

NCBI Gene: 27240 ENSG00000137078 UniProt: Q9NP91 OMIM: 604964

The SIT1 protein functions as a sodium- and chloride-dependent transporter that mediates uptake of imino acids like proline and pipecolate, as well as glycine, playing a key role in regulating proline and glycine homeostasis in the brain and modulating NMDAR currents. Mutations cause autosomal recessive intellectual developmental disorder with seizures and language delay, typically presenting in early childhood. This gene shows low constraint to loss-of-function variation, which is consistent with its recessive inheritance pattern.

OMIM ResearchSummary from RefSeq, UniProt

Enables kinase binding activity. Involved in regulation of T cell activation. Located in plasma membrane. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtHyperglycinuria

UniProtIminoglycinuria

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.19

LOEUF

Multiple*

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.19LOEUF

pLI 0.001

Z-score 1.16

OE 0.60 (0.33–1.19)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

1.17Z-score

OE missense 0.69 (0.58–0.83)

79 obs / 114.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.60 (0.33–1.19)

0≤0.351.4

Missense OE?0.69 (0.58–0.83)

0≤0.61.4

Synonymous OE?0.97

0≤1.21.6

LoF obs/exp: 6 / 10.0Missense obs/exp: 79 / 114.1Syn Z: 0.15

Background carrier burden — how many people carry a rare variant somewhere in SIT1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 220

241 rare PASS variants

Rare truncating (LoF)

1 in 2,600

32 rare PASS variants

Rare synonymous (reference)

1 in 590

123 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for SIT1. 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 270	1 in 8,500
South Asian	~43k	1 in 200	1 in 5,300
Remaining (unassigned)	~30k	1 in 220	≈ 1 in 30,000
European (Finnish)	~27k	1 in 1,100	≈ 1 in 27,000
Admixed American	~22k	1 in 180	≈ 1 in 4,600
African / African American	~21k	1 in 140	≈ 1 in 4,600
East Asian	~20k	1 in 210	≈ 1 in 19,000
Ashkenazi Jewish	~13k	1 in 810	none seen
Middle Eastern	~2,884	1 in 290	none seen

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): All 5 coding exons well covered in gnomAD exomes and genomes.? see exons ↓