SLC25A22

Chr 11AR

solute carrier family 25 member 22

Also known as: DEE3, EIEE3, GC-1, GC1, NET44

NCBI Gene: 79751ENSG00000177542UniProt: Q9H936

This gene encodes a mitochondrial glutamate carrier. Mutations in this gene are associated with early infantile epileptic encephalopathy. Multiple alternatively spliced variants, encoding the same protein, have been identified.[provided by RefSeq, Jul 2010]

Primary Disease Associations & Inheritance

Developmental and epileptic encephalopathy 3MIM #609304
AR
585
ClinVar variants
37
Pathogenic / LP
0.01
pLI score
0
Active trials
Clinical Summary— SLC25A22
🧬
Gene-Disease Validity (ClinGen)
developmental and epileptic encephalopathy · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.01) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
37 Pathogenic / Likely Pathogenic· 253 VUS of 585 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.81LOEUF
pLI 0.007
Z-score 2.09
OE 0.41 (0.22–0.81)
Tolerant

Typical tolerance to LoF variation

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
0.91Z-score
OE missense 0.82 (0.72–0.93)
168 obs / 204.8 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.41 (0.22–0.81)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.82 (0.72–0.93)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.29
0≤1.21.6
LoF obs/exp: 6 / 14.6Missense obs/exp: 168 / 204.8Syn Z: -2.20

ClinVar Variant Classifications

585 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic31
Likely Pathogenic6
VUS253
Likely Benign251
Benign21
Conflicting23
31
Pathogenic
6
Likely Pathogenic
253
VUS
251
Likely Benign
21
Benign
23
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
5
1
25
0
31
Likely Pathogenic
4
0
2
0
6
VUS
3
169
79
2
253
Likely Benign
0
2
128
121
251
Benign
0
0
21
0
21
Conflicting
—23
Total12172255123585

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

View in ClinVar →

Protein Context — Lollipop Plot

SLC25A22 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

SLC25A22-related epileptic encephalopathy, early infantile

strong
ARUndeterminedAltered Gene Product Structure
Dev. Disorders
G2P ↗
missense variantinframe deletioninframe insertion

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Developmental and epileptic encephalopathy 3

MIM #609304

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Targeting Glutamine Metabolism Transporter SLC25A22 Enhances CD8+ T-Cell Function and Anti-PD-1 Therapy Efficacy in Cervical Squamous Cell Carcinoma: Integrated Metabolomics, Transcriptomics and T-Cell-Incorporated Tumor Organoid Studies.
Ren T et al.·Adv Sci (Weinh)
2025
The phenotype caused by recessive variations in SLC25A22: Report of a new case and literature review.
André MV et al.·Arch Pediatr
2021Review
Report on three additional patients and genotype-phenotype correlation in SLC25A22-related disorders group.
Lemattre C et al.·Eur J Hum Genet
2019Cohort
Severe early-onset developmental and epileptic encephalopathy (DEE) associated with novel compound heterozygous pathogenic variants in SLC25A22: Case report and literature review.
Giacomini T et al.·Seizure
2019Review
De novo mutation in SLC25A22 gene: expansion of the clinical and electroencephalographic phenotype.
Nicotera AG et al.·J Neurogenet
2021Case report
Diagnostic Approach to Genetic Causes of Early-Onset Epileptic Encephalopathy.
Gürsoy S et al.·J Child Neurol
2016Review
SLC25A22 is a novel gene for migrating partial seizures in infancy.
Poduri A et al.·Ann Neurol
2013
Mutations in SLC25A22: hyperprolinaemia, vacuolated fibroblasts and presentation with developmental delay.
Reid ES et al.·J Inherit Metab Dis
2017
Ohtahara syndrome with emphasis on recent genetic discovery.
Pavone P et al.·Brain Dev
2012Review
Mutations in the mitochondrial glutamate carrier SLC25A22 in neonatal epileptic encephalopathy with suppression bursts.
Molinari F et al.·Clin Genet
2009
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools