Salla disease

Summary

Salla disease (MONDO:0011449) is a disease caused by SLC17A5 (GenCC Definitive), with 4 cohort genes and 2 clinical trials.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: SLC17A5 (GenCC Definitive)
• Cohort genes: 4
• ClinVar variants: 645
• Clinical trials: 2

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	<1 / 1 000 000		Worldwide	Validated
Prevalence at birth	1-9 / 100 000	1.59	Sweden	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	Salla disease
Mondo ID	MONDO:0011449
OMIM	604369
Orphanet	309334
NCIT	C85067
SNOMED CT	87074006
UMLS	C1096903
MedGen	203368
GARD	0004754
MedDRA	10067531
Is cancer (heuristic)	no

Also known as: Salla disease · SD · sialic acid storage disease

Data availability: 645 ClinVar variants · 5 GenCC gene-disease records · 12 cell lines.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › inborn carbohydrate metabolic disorder › disorder of carbohydrate transmembrane transport and absorption › Salla disease

Related subtypes (13): congenital sucrase-isomaltase deficiency, congenital lactase deficiency, free sialic acid storage disease, infantile form, dystonia 9, hereditary cryohydrocytosis with reduced stomatin, exercise-induced hyperinsulinism, juvenile cataract-microcornea-renal glucosuria syndrome, diarrhea-vomiting due to trehalase deficiency, childhood onset GLUT1 deficiency syndrome 2, chronic diarrhea due to glucoamylase deficiency, intermediate severe Salla disease, glucose transport disorder, autosomal recessive non-syndromic intellectual disability

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

600 retrieved; paginated sample, class counts are floors:

268 likely benign, 139 uncertain significance, 77 likely pathogenic, 52 pathogenic, 32 pathogenic/likely pathogenic, 21 benign, 8 conflicting classifications of pathogenicity, 3 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1071718	NC_000006.11:g.(?72596727)(74363609_?)del	CGAS	Pathogenic	criteria provided, single submitter
1355900	NM_012434.5(SLC17A5):c.1A>T (p.Met1Leu)	LOC129996727	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
167694	NM_012434.5(SLC17A5):c.43G>T (p.Glu15Ter)	LOC129996727	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1923520	NM_012434.5(SLC17A5):c.1A>C (p.Met1Leu)	LOC129996727	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2850562	NM_012434.5(SLC17A5):c.3del (p.Met1fs)	LOC129996727	Pathogenic	criteria provided, single submitter
2891846	NM_012434.5(SLC17A5):c.1del (p.Met1*)	LOC129996727	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2005981	NM_012434.5(SLC17A5):c.329G>A (p.Trp110Ter)	LOC132089454	Pathogenic	criteria provided, single submitter
2678779	NM_012434.5(SLC17A5):c.294_310del	LOC132089454	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
370442	NM_012434.5(SLC17A5):c.349dup (p.Tyr117fs)	LOC132089454	Pathogenic	criteria provided, single submitter
649623	NC_000006.12:g.(?73641681)(73644613_?)del	LOC132089454	Pathogenic	criteria provided, single submitter
1068854	NM_012434.5(SLC17A5):c.795_796insTT (p.Ile266fs)	SLC17A5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1071719	NC_000006.11:g.(?74345095)(74345233_?)del	SLC17A5	Pathogenic	criteria provided, single submitter
1072471	NM_012434.5(SLC17A5):c.144dup (p.Gly49fs)	SLC17A5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1073504	NM_012434.5(SLC17A5):c.157del (p.Val53fs)	SLC17A5	Pathogenic	criteria provided, single submitter
1073614	NC_000006.11:g.(?74345095)(74346440_?)del	SLC17A5	Pathogenic	criteria provided, single submitter
1074913	NM_012434.5(SLC17A5):c.146del (p.Gly49fs)	SLC17A5	Pathogenic	criteria provided, single submitter
1075886	NM_012434.5(SLC17A5):c.976G>T (p.Glu326Ter)	SLC17A5	Pathogenic	criteria provided, single submitter
1252083	NM_012434.5(SLC17A5):c.744_747del (p.Ser249fs)	SLC17A5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1252085	NM_012434.5(SLC17A5):c.1111+1G>A	SLC17A5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1362038	NM_012434.5(SLC17A5):c.699del (p.Phe233fs)	SLC17A5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1364804	NM_012434.5(SLC17A5):c.579_580insTTTTTTTTTTTTTTTTTTTTNNNNNNNNNNCCCCCCCCCCCTCCCTCCCGGACGGGGCGGCTGGCCGGGCAGAGGGGCTCCTCACTTCCCAGTAGGGGCGGCCGGGCAGAGGGGGCTCCCCCTCTT (p.Leu193_Glu194insPhePhePhePhePhePheXaaXaaXaaXaaProProProProProSerArgThrGlyArgLeuAlaGlyGlnArgGlySerSerLeuProSerArgGlyGlyArgAlaGluGlyAlaProProLeu)	SLC17A5	Pathogenic	criteria provided, single submitter
1412336	NM_012434.5(SLC17A5):c.860_863dup (p.Leu289fs)	SLC17A5	Pathogenic	criteria provided, single submitter
1420974	NC_000006.11:g.(?74325018)(74325190_?)del	SLC17A5	Pathogenic	criteria provided, single submitter
1447940	NM_012434.5(SLC17A5):c.964_976del (p.Phe322fs)	SLC17A5	Pathogenic	criteria provided, single submitter
1454733	NM_012434.5(SLC17A5):c.738G>A (p.Trp246Ter)	SLC17A5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1457044	NM_012434.5(SLC17A5):c.829C>T (p.Gln277Ter)	SLC17A5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1458010	NM_012434.5(SLC17A5):c.998del (p.Leu333fs)	SLC17A5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1460030	NC_000006.11:g.(?74304790)(74354336_?)del	SLC17A5	Pathogenic	criteria provided, single submitter
1460247	NC_000006.11:g.(?74304790)(74310174_?)del	SLC17A5	Pathogenic	criteria provided, single submitter
1460316	NC_000006.11:g.(?74331507)(74331705_?)del	SLC17A5	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · Orphanet: 6 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
SLC17A5	Definitive	Autosomal recessive	Salla disease	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SLC17A5	Orphanet:309324	Free sialic acid storage disease, infantile form
SLC17A5	Orphanet:309331	Intermediate severe Salla disease
SLC17A5	Orphanet:309334	Salla disease
RAG2	Orphanet:157949	Combined immunodeficiency with granulomatosis
RAG2	Orphanet:331206	Severe combined immunodeficiency due to complete RAG1/2 deficiency
RAG2	Orphanet:39041	Omenn syndrome

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SLC17A5	HGNC:10933	ENSG00000119899	Q9NRA2	Sialin	gencc,clinvar
CGAS	HGNC:21367	ENSG00000164430	Q8N884	Cyclic GMP-AMP synthase	clinvar
EEF1A1	HGNC:3189	ENSG00000156508	P68104	Elongation factor 1-alpha 1	clinvar
RAG2	HGNC:9832	ENSG00000175097	P55895	V(D)J recombination-activating protein 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SLC17A5	Sialin	Multifunctional anion transporter that operates via two distinct transport mechanisms, namely proton-coupled anion cotransport and membrane potential-dependent anion transport.
CGAS	Cyclic GMP-AMP synthase	Nucleotidyltransferase that catalyzes the formation of cyclic GMP-AMP (2’,3’-cGAMP) from ATP and GTP and plays a key role in innate immunity.
EEF1A1	Elongation factor 1-alpha 1	Translation elongation factor that catalyzes the GTP-dependent binding of aminoacyl-tRNA (aa-tRNA) to the A-site of ribosomes during the elongation phase of protein synthesis.
RAG2	V(D)J recombination-activating protein 2	Core component of the RAG complex, a multiprotein complex that mediates the DNA cleavage phase during V(D)J recombination.

Protein-family classification

Druggable: 2 · Difficult: 1 · Unknown: 1 · Druggable fraction: 0.5

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Transporter	1	19.4×	0.202
Enzyme (other)	1	3.0×	0.538
Transcription factor	1	2.1×	0.538
Other/Unknown	1	0.5×	0.962

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SLC17A5	Transporter	yes		MFS, MFS_dom, MFS_trans_sf
CGAS	Enzyme (other)	yes	2.7.7.86	MAB21L/cGLR, Mab-21-like_nuc_Trfase, Mab-21_HhH/H2TH-like
EEF1A1	Other/Unknown	no		T_Tr_GTP-bd_dom, EFTu-like_2, Transl_elong_EF1A_euk/arc
RAG2	Transcription factor	no		RAG2, Znf_FYVE_PHD, Gal_Oxase/kelch_b-propeller

Expression context

Cohort genes with no expression data: 0.

3 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
stromal cell of endometrium	2
corpus epididymis	1
mucosa of sigmoid colon	1
buccal mucosa cell	1
pancreatic ductal cell	1
sperm	1
embryo	1
ventricular zone	1
bone marrow	1
left lobe of thyroid gland	1
thymus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SLC17A5	264	ubiquitous	marker	corpus epididymis, stromal cell of endometrium, mucosa of sigmoid colon
CGAS	213	ubiquitous	yes	pancreatic ductal cell, sperm, buccal mucosa cell
EEF1A1	273	ubiquitous	marker	stromal cell of endometrium, embryo, ventricular zone
RAG2	119	tissue_specific	marker	thymus, bone marrow, left lobe of thyroid gland

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CGAS	2,465
RAG2	2,319
EEF1A1	1,455
SLC17A5	1,170

Structural data

PDB: 4 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CGAS	Q8N884	107
EEF1A1	P68104	17
SLC17A5	Q9NRA2	7
RAG2	P55895	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 26. Enrichment computed across 4 evidence-associated genes (4 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective SLC17A5 causes Salla disease (SD) and ISSD	1	2855.0×	0.009	SLC17A5
Organic anion transport by SLC5/17/25 transporters	1	356.9×	0.029	SLC17A5
STING mediated induction of host immune responses	1	259.6×	0.029	CGAS
Hyaluronan degradation	1	178.4×	0.029	SLC17A5
Protein methylation	1	167.9×	0.029	EEF1A1
Chaperone Mediated Autophagy	1	124.1×	0.029	EEF1A1
HSF1 activation	1	95.2×	0.029	EEF1A1
Dengue virus activates/modulates innate and adaptive immune responses	1	84.0×	0.029	CGAS
Sialic acid metabolism	1	81.6×	0.029	SLC17A5
Interleukin-7 signaling	1	79.3×	0.029	RAG2
SARS-CoV-1 modulates host translation machinery	1	77.2×	0.029	EEF1A1
Synthesis of substrates in N-glycan biosythesis	1	73.2×	0.029	SLC17A5
Eukaryotic Translation Elongation	1	69.6×	0.029	EEF1A1
Biosynthesis of the N-glycan precursor (dolichol lipid-linked oligosaccharide, LLO) and transfer to a nascent protein	1	51.9×	0.034	SLC17A5
SLC transporter disorders	1	51.0×	0.034	SLC17A5
Disorders of transmembrane transporters	1	34.8×	0.043	SLC17A5
MAPK6/MAPK4 signaling	1	34.0×	0.043	RAG2
R-HSA-425393	1	32.4×	0.043	SLC17A5
Peptide chain elongation	1	31.7×	0.043	EEF1A1
Asparagine N-linked glycosylation	1	15.0×	0.082	SLC17A5
SLC-mediated transmembrane transport	1	14.8×	0.082	SLC17A5
Transport of small molecules	1	6.3×	0.177	SLC17A5
Neutrophil degranulation	1	5.8×	0.184	EEF1A1
Post-translational protein modification	1	4.8×	0.209	SLC17A5
Disease	1	3.3×	0.283	SLC17A5
Metabolism of proteins	1	3.1×	0.286	SLC17A5

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
sialic acid transport	1	4213.0×	0.005	SLC17A5
B cell homeostatic proliferation	1	2106.5×	0.005	RAG2
carbohydrate derivative transport	1	2106.5×	0.005	SLC17A5
pre-B cell allelic exclusion	1	1404.3×	0.005	RAG2
mature B cell differentiation involved in immune response	1	1053.2×	0.005	RAG2
DN2 thymocyte differentiation	1	1053.2×	0.005	RAG2
B cell lineage commitment	1	842.6×	0.005	RAG2
T cell lineage commitment	1	842.6×	0.005	RAG2
cGAS/STING signaling pathway	1	842.6×	0.005	CGAS
regulation of chaperone-mediated autophagy	1	842.6×	0.005	EEF1A1
negative regulation of T cell differentiation in thymus	1	702.2×	0.005	RAG2
paracrine signaling	1	702.2×	0.005	CGAS
neurotransmitter loading into synaptic vesicle	1	702.2×	0.005	SLC17A5
regulation of immunoglobulin production	1	601.9×	0.005	CGAS
V(D)J recombination	1	526.6×	0.005	RAG2
regulation of T cell activation	1	468.1×	0.006	CGAS
host-mediated activation of viral genome replication	1	421.3×	0.006	EEF1A1
monoatomic anion transport	1	351.1×	0.006	SLC17A5
positive regulation of organ growth	1	351.1×	0.006	RAG2
positive regulation of cellular senescence	1	324.1×	0.007	CGAS
translational elongation	1	300.9×	0.007	EEF1A1
cellular response to exogenous dsRNA	1	263.3×	0.007	CGAS
negative regulation of cGAS/STING signaling pathway	1	263.3×	0.007	CGAS
pattern recognition receptor signaling pathway	1	247.8×	0.007	CGAS
cytoplasmic pattern recognition receptor signaling pathway	1	221.7×	0.008	CGAS
organ growth	1	183.2×	0.009	RAG2
negative regulation of double-strand break repair via homologous recombination	1	156.0×	0.010	CGAS
positive regulation of defense response to virus by host	1	131.7×	0.012	CGAS
activation of innate immune response	1	120.4×	0.012	CGAS
determination of adult lifespan	1	108.0×	0.013	CGAS

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 3

Druggability breadth: 3 of 4 evidence-associated genes (75%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
CGAS	HYDROXYCHLOROQUINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CGAS	2	4
SLC17A5	0	0
EEF1A1	0	0
RAG2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
HYDROXYCHLOROQUINE	4	CGAS
QUINACRINE	4	CGAS

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
CGAS	94	Binding:92, ADMET:2
EEF1A1	15	Binding:15
SLC17A5	14	Binding:14

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CGAS	2.7.7.86	cyclic GMP-AMP synthase

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

2 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
HYDROXYCHLOROQUINE	4	CGAS
QUINACRINE	4	CGAS

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	CGAS
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	SLC17A5
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	EEF1A1, RAG2

Undrugged target profiles

3 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
SLC17A5	14	—
EEF1A1	15	—
RAG2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03047369	Not specified	RECRUITING	The Myelin Disorders Biorepository Project
NCT02699190	Not specified	COMPLETED	LeukoSEQ: Whole Genome Sequencing as a First-Line Diagnostic Tool for Leukodystrophies