AASS

Summary

AASS (aminoadipate-semialdehyde synthase, HGNC:17366) is a protein-coding gene on chromosome 7q31.32, encoding Alpha-aminoadipic semialdehyde synthase, mitochondrial (Q9UDR5). Bifunctional enzyme that catalyzes the first two steps in lysine degradation.

This gene encodes a bifunctional enzyme that catalyzes the first two steps in the mammalian lysine degradation pathway. The N-terminal and the C-terminal portions of this enzyme contain lysine-ketoglutarate reductase and saccharopine dehydrogenase activity, respectively, resulting in the conversion of lysine to alpha-aminoadipic semialdehyde. Mutations in this gene are associated with familial hyperlysinemia.

Source: NCBI Gene 10157 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hyperlysinemia (Definitive, ClinGen)
• GWAS associations: 1
• Clinical variants (ClinVar): 333 total — 24 pathogenic, 12 likely-pathogenic
• Phenotypes (HPO): 78
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_005763

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17366
Approved symbol	AASS
Name	aminoadipate-semialdehyde synthase
Location	7q31.32
Locus type	gene with protein product
Status	Approved
Aliases	LORSDH, LKRSDH, LKR/SDH
Ensembl gene	ENSG00000008311
Ensembl biotype	protein_coding
OMIM	605113
Entrez	10157

Gene structure

Transcript identifiers

Ensembl transcripts: 35 — 16 nonsense_mediated_decay, 14 protein_coding, 4 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000358954, ENST00000393376, ENST00000417368, ENST00000426162, ENST00000431170, ENST00000460376, ENST00000473553, ENST00000679402, ENST00000679419, ENST00000679511, ENST00000679579, ENST00000679659, ENST00000679721, ENST00000679764, ENST00000679818, ENST00000679847, ENST00000679864, ENST00000680080, ENST00000681213, ENST00000681314, ENST00000681318, ENST00000681387, ENST00000681434, ENST00000681511, ENST00000681626, ENST00000681708, ENST00000681907, ENST00000881844, ENST00000881845, ENST00000912145, ENST00000912146, ENST00000912147, ENST00000912148, ENST00000912149, ENST00000962616

RefSeq mRNA: 1 — MANE Select: NM_005763 NM_005763

CCDS: CCDS5783

Canonical transcript exons

ENST00000417368 — 24 exons

Exon	Start	End
ENSE00000443746	122129361	122129537
ENSE00000443747	122126375	122126459
ENSE00000443749	122118307	122118453
ENSE00000443751	122116633	122116760
ENSE00000443753	122113598	122113720
ENSE00000443757	122098745	122098866
ENSE00000719524	122113118	122113229
ENSE00000719528	122115074	122115222
ENSE00000719551	122116879	122116957
ENSE00000719559	122118563	122118630
ENSE00001408512	122133517	122133741
ENSE00001412298	122144161	122144249
ENSE00001934772	122073549	122076607
ENSE00003464725	122081500	122081595
ENSE00003484817	122101621	122101680
ENSE00003506650	122098450	122098576
ENSE00003507095	122091703	122091843
ENSE00003538707	122093048	122093158
ENSE00003546085	122092843	122092951
ENSE00003557196	122077838	122078014
ENSE00003630764	122086012	122086179
ENSE00003664061	122078862	122078950
ENSE00003685128	122079597	122079712
ENSE00003686944	122101371	122101438

Expression profiles

Bgee: expression breadth ubiquitous, 260 present calls, max score 96.66.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 17.5114 / max 533.4810, expressed in 1435 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
85921	14.7578	1407
85918	1.4424	448
85920	0.8676	353
85922	0.4436	253

Top tissues by expression

288 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
mucosa of stomach	UBERON:0001199	96.66	gold quality
left ovary	UBERON:0002119	95.91	gold quality
right ovary	UBERON:0002118	95.16	gold quality
tibial nerve	UBERON:0001323	95.03	gold quality
right lobe of liver	UBERON:0001114	93.99	gold quality
left uterine tube	UBERON:0001303	93.58	gold quality
right lung	UBERON:0002167	93.53	gold quality
sural nerve	UBERON:0015488	92.98	gold quality
popliteal artery	UBERON:0002250	92.09	gold quality
tibial artery	UBERON:0007610	92.08	gold quality
body of uterus	UBERON:0009853	91.69	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	91.40	gold quality
ovary	UBERON:0000992	91.27	gold quality
ventricular zone	UBERON:0003053	91.26	gold quality
lower esophagus muscularis layer	UBERON:0035833	91.18	gold quality
lower esophagus	UBERON:0013473	91.13	gold quality
calcaneal tendon	UBERON:0003701	90.77	gold quality
body of pancreas	UBERON:0001150	90.67	gold quality
aorta	UBERON:0000947	90.43	gold quality
left coronary artery	UBERON:0001626	89.92	gold quality
descending thoracic aorta	UBERON:0002345	89.80	gold quality
endocervix	UBERON:0000458	89.48	gold quality
liver	UBERON:0002107	89.02	gold quality
omental fat pad	UBERON:0010414	88.66	gold quality
peritoneum	UBERON:0002358	88.62	gold quality
upper lobe of left lung	UBERON:0008952	88.62	gold quality
coronary artery	UBERON:0001621	88.58	gold quality
thoracic aorta	UBERON:0001515	88.51	gold quality
tendon of biceps brachii	UBERON:0008188	88.47	gold quality
ascending aorta	UBERON:0001496	88.37	gold quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	24.13
E-GEOD-93593	yes	14.95
E-MTAB-9388	yes	10.82
E-ENAD-27	yes	3.98
E-MTAB-6524	no	369.57
E-CURD-53	no	208.12

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

107 targeting AASS, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-6798-5P	100.00	65.77	699
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-9983-3P	99.94	71.48	3631

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 4)

• Isolation and characterization of the mouse ortholog. (PMID:10567240)
• Hyperlysinemia is caused by mutations in AASS (PMID:23570448)
• Mitochondrial NADPH is crucial for AASS function (PMID:24847004)
• GR and KLF15 physically interact via low affinity GR binding sites within glucocorticoid response elements (GREs) for PRODH and AASS that contribute to combinatorial regulation with KLF15. (PMID:26088140)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	aass	ENSDARG00000051816
mus_musculus	Aass	ENSMUSG00000029695
rattus_norvegicus	Aass	ENSRNOG00000039494
drosophila_melanogaster	LKRSDH	FBGN0286198
caenorhabditis_elegans		WBGENE00019819

Protein

Protein identifiers

Alpha-aminoadipic semialdehyde synthase, mitochondrial — Q9UDR5 (reviewed: Q9UDR5)

Alternative names: LKR/SDH

All UniProt accessions (15): Q9UDR5, A0A7P0T834, A0A7P0T8W7, A0A7P0T9N4, A0A7P0TA09, A0A7P0TA62, A0A7P0TAY5, A0A7P0TB07, A0A7P0TBD2, A0A7P0Z402, A0A7P0Z428, A0A7P0Z4M3, A4D0W4, F8WAH1, F8WE53

UniProt curated annotations — full annotation on UniProt →

Function. Bifunctional enzyme that catalyzes the first two steps in lysine degradation.

Subunit / interactions. Homotetramer.

Subcellular location. Mitochondrion.

Tissue specificity. Expressed in all 16 tissues examined with highest expression in the liver.

Disease relevance. Hyperlysinemia, 1 (HYPLYS1) [MIM:238700] An autosomal recessive metabolic condition with variable clinical features. Some patients present with non-specific seizures, hypotonia, or mildly delayed psychomotor development, and increased serum lysine and pipecolic acid on laboratory analysis. However, about half of the probands are reported to be asymptomatic, and hyperlysinemia is generally considered to be a benign metabolic variant. The disease is caused by variants affecting the gene represented in this entry. In hyperlysinemia 1, both enzymatic functions of AASS are defective and patients have increased serum lysine and possibly increased saccharopine. Some individuals, however, retain significant amounts of lysine-ketoglutarate reductase and present with saccharopinuria, a metabolic condition with few, if any, clinical manifestations. 2,4-dienoyl-CoA reductase deficiency (DECRD) [MIM:616034] A rare, autosomal recessive, inborn error of polyunsaturated fatty acids and lysine metabolism, resulting in mitochondrial dysfunction. Affected individuals have a severe encephalopathy with neurologic and metabolic abnormalities beginning in early infancy. Laboratory studies show increased C10:2 carnitine levels and hyperlysinemia. The protein represented in this entry is involved in disease pathogenesis. A selective decrease in mitochondrial NADP(H) levels due to NADK2 mutations causes a deficiency of NADPH-dependent mitochondrial enzymes, such as DECR1 and AASS.

Domain organisation. The N-terminal and the C-terminal domains contain respectively the lysine ketoglutarate reductase and saccharopine dehydrogenase activity.

Induction. Induced by starvation.

Pathway. Amino-acid degradation; L-lysine degradation via saccharopine pathway; glutaryl-CoA from L-lysine: step 1/6. Amino-acid degradation; L-lysine degradation via saccharopine pathway; glutaryl-CoA from L-lysine: step 2/6.

Similarity. In the N-terminal section; belongs to the AlaDH/PNT family. In the C-terminal section; belongs to the saccharopine dehydrogenase family.

RefSeq proteins (1): NP_005754* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR005097	Sacchrp_dh_NADP-bd	Domain
IPR007698	AlaDH/PNT_NAD(H)-bd	Domain
IPR007886	AlaDH/PNT_N	Domain
IPR032095	Sacchrp_dh-like_C	Domain
IPR036291	NAD(P)-bd_dom_sf	Homologous_superfamily
IPR051168	AASS	Family

Pfam: PF03435, PF05222, PF16653

Catalyzed reactions (Rhea), 2 shown:

• L-saccharopine + NADP(+) + H2O = L-lysine + 2-oxoglutarate + NADPH + H(+) (RHEA:19373)
• L-saccharopine + NAD(+) + H2O = (S)-2-amino-6-oxohexanoate + L-glutamate + NADH + H(+) (RHEA:24520)

UniProt features (142 total): helix 46, strand 45, modified residue 25, binding site 14, turn 7, region of interest 2, transit peptide 1, chain 1, sequence conflict 1

Structure

Experimental structures (PDB)

9 structures.

PDB	Method	Resolution (Å)
5O1P	X-RAY DIFFRACTION	1.9
8E8T	X-RAY DIFFRACTION	2.18
5O1N	X-RAY DIFFRACTION	2.28
8DDA	X-RAY DIFFRACTION	2.4
8E8V	X-RAY DIFFRACTION	2.45
5O1O	X-RAY DIFFRACTION	2.48
5L76	X-RAY DIFFRACTION	2.57
8E8U	X-RAY DIFFRACTION	2.65
5L78	X-RAY DIFFRACTION	2.68

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UDR5-F1	90.73	0.77

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (14): 577–578; 577; 603; 604; 604; 605; 703; 724–726; 488; 512; 516; 533 …

Post-translational modifications (25): 48, 56, 93, 93, 128, 138, 138, 274, 286, 286, 333, 458, 458, 523, 523, 535, 535, 584, 584, 707 …

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-71064	Lysine catabolism
R-HSA-1430728	Metabolism
R-HSA-71291	Metabolism of amino acids and derivatives

MSigDB gene sets: 319 (showing top): MODULE_255, GOBP_ALPHA_AMINO_ACID_METABOLIC_PROCESS, MODULE_317, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_ACETYL_COA_METABOLIC_PROCESS, RODWELL_AGING_KIDNEY_NO_BLOOD_DN, GOBP_NUCLEOBASE_CONTAINING_SMALL_MOLECULE_METABOLIC_PROCESS, SHETH_LIVER_CANCER_VS_TXNIP_LOSS_PAM4, SHEDDEN_LUNG_CANCER_GOOD_SURVIVAL_A4, GOBP_AMIDE_METABOLIC_PROCESS, GOBP_ORGANIC_ACID_CATABOLIC_PROCESS, CAIRO_HEPATOBLASTOMA_DN, KEGG_LYSINE_DEGRADATION, GOBP_ORGANIC_ACID_METABOLIC_PROCESS, HELLER_HDAC_TARGETS_SILENCED_BY_METHYLATION_UP

GO Biological Process (6): negative regulation of transcription by RNA polymerase II (GO:0000122), obsolete lysine catabolic process (GO:0006554), obsolete L-lysine biosynthetic process via aminoadipic acid (GO:0019878), obsolete L-lysine catabolic process to acetyl-CoA via L-saccharopine (GO:0033512), obsolete lysine metabolic process (GO:0006553), L-lysine catabolic process (GO:0019477)

GO Molecular Function (8): transcription corepressor activity (GO:0003714), saccharopine dehydrogenase activity (GO:0004753), saccharopine dehydrogenase (NAD+, L-lysine-forming) activity (GO:0004754), histone binding (GO:0042393), saccharopine dehydrogenase (NADP+, L-lysine-forming) activity (GO:0047130), saccharopine dehydrogenase (NAD+, L-glutamate-forming) activity (GO:0047131), catalytic activity (GO:0003824), oxidoreductase activity (GO:0016491)

GO Cellular Component (5): nucleus (GO:0005634), cytoplasm (GO:0005737), mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759), cytosol (GO:0005829)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Metabolism of amino acids and derivatives	1
Metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
saccharopine dehydrogenase activity	3
negative regulation of DNA-templated transcription	2
intracellular membrane-bounded organelle	2
cellular anatomical structure	2
cytoplasm	2
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
L-amino acid catabolic process	1
proteinogenic amino acid catabolic process	1
transcription coregulator activity	1
oxidoreductase activity, acting on the CH-NH group of donors, NAD or NADP as acceptor	1
protein binding	1
molecular_function	1
catalytic activity	1
intracellular anatomical structure	1
mitochondrion	1
intracellular organelle lumen	1

Protein interactions and networks

STRING

1198 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
AASS	ASS1	P00966	704
AASS	HGD	Q93099	558
AASS	ALDH18A1	P54886	528
AASS	HAL	P42357	512
AASS	TAT	P17735	511
AASS	AMT	P48728	496
AASS	SDS	P20132	493
AASS	AADAT	Q8N5Z0	485
AASS	GPX6	P59796	483
AASS	PIPOX	Q9P0Z9	477
AASS	OAT	P04181	476
AASS	AASDH	Q4L235	472
AASS	NME8	Q8N427	451
AASS	DMAC2	Q9NW81	447
AASS	SLC25A29	Q8N8R3	446

IntAct

47 interactions, top by confidence:

A	B	Type	Score
GET4	GET3	psi-mi:“MI:0914”(association)	0.800
	PMPCB	psi-mi:“MI:0914”(association)	0.640
NDUFA13	NDUFS8	psi-mi:“MI:0914”(association)	0.640
VPS37D	CRTAP	psi-mi:“MI:0914”(association)	0.530
FAM174A	BLTP3B	psi-mi:“MI:0914”(association)	0.530
MYC	ILVBL	psi-mi:“MI:0914”(association)	0.350
HSCB	RBP5	psi-mi:“MI:0914”(association)	0.350
P2RY6	RAVER1	psi-mi:“MI:0914”(association)	0.350
M		psi-mi:“MI:0914”(association)	0.350
TRAV20	MAP2K7	psi-mi:“MI:0914”(association)	0.350
ARHGEF39	ACAA1	psi-mi:“MI:0914”(association)	0.350
GPR45	VWA8	psi-mi:“MI:0914”(association)	0.350
ACKR3	PDE2A	psi-mi:“MI:0914”(association)	0.350
ADGRG5	SLC33A1	psi-mi:“MI:0914”(association)	0.350
AURKB	VWA8	psi-mi:“MI:0914”(association)	0.350
CCNI2	ZNF609	psi-mi:“MI:0914”(association)	0.350
CD80	RIMOC1	psi-mi:“MI:0914”(association)	0.350
CXCR3	RIMOC1	psi-mi:“MI:0914”(association)	0.350
FPR1	NBAS	psi-mi:“MI:0914”(association)	0.350
GZMH	PCDH7	psi-mi:“MI:0914”(association)	0.350
PRKACG	IDE	psi-mi:“MI:0914”(association)	0.350
PTH2R	SPTLC2	psi-mi:“MI:0914”(association)	0.350
SFXN3	ACSL1	psi-mi:“MI:0914”(association)	0.350
SLC2A12	NBAS	psi-mi:“MI:0914”(association)	0.350
MFSD4A	TIMM23	psi-mi:“MI:0914”(association)	0.350
SLC2A5	ESYT2	psi-mi:“MI:0914”(association)	0.350
SLC35E2B	ERLIN1	psi-mi:“MI:0914”(association)	0.350
SLC39A2	AGPAT2	psi-mi:“MI:0914”(association)	0.350

BioGRID (88): ACADM (Co-fractionation), AASS (Affinity Capture-MS), AASS (Affinity Capture-MS), AASS (Proximity Label-MS), AASS (Proximity Label-MS), AASS (Proximity Label-MS), AASS (Proximity Label-MS), AASS (Proximity Label-MS), AASS (Proximity Label-MS), AASS (Co-fractionation), AASS (Co-fractionation), AASS (Co-fractionation), AASS (Co-fractionation), AASS (Co-fractionation), AASS (Co-fractionation)

ESM2 similar proteins: A0A095C6S0, A0A095CCB2, A0A0F7TXA5, A0A142C7A0, A0A2G5IC53, A0A2I1BSU0, A0A499UB99, A2V9Y8, A8NS27, A8WXM1, C0HMB0, C4R4G9, C4R6B0, C5H881, D4B1Y1, G2QA95, G5EB76, I1RN13, J4W6X9, J9VPE7, J9VRT1, O13492, O35078, O43029, O45307, P00371, P14920, P18894, P21334, P22942, P24552, P36842, P36858, P51659, P51660, P54898, P54982, P80324, Q0CRI5, Q0CS91

Diamond homologs: A2VCW9, A8E657, O59711, P38999, Q54NG9, Q99K67, Q9P4R4, Q9SMZ4, Q9UDR5, P38997, Q8YMD9

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 69 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	8	101.4×	6e-13
Activation of BAD and translocation to mitochondria	7	100.5×	3e-11
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	7	88.7×	6e-11
Activation of BH3-only proteins	7	65.6×	5e-10
RHO GTPases activate PKNs	8	47.9×	3e-10
Intrinsic Pathway for Apoptosis	7	38.7×	2e-08
FOXO-mediated transcription	5	31.7×	1e-05
SARS-CoV-1-host interactions	7	23.2×	8e-07

GO biological processes:

GO term	Partners	Fold	FDR
protein targeting	5	29.5×	3e-04
intracellular protein localization	7	11.8×	5e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

333 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	24
Likely pathogenic	12
Uncertain significance	159
Likely benign	75
Benign	33

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
100642	NM_005763.4(AASS):c.2662+1_2662+5delinsTT	Pathogenic
100643	NM_005763.4(AASS):c.874A>G (p.Ile292Val)	Pathogenic
100644	NM_005763.4(AASS):c.976_977del (p.Gln326fs)	Pathogenic
100645	NM_005763.4(AASS):c.1925C>G (p.Ser642Ter)	Pathogenic
100647	NM_005763.4(AASS):c.1256T>G (p.Leu419Arg)	Pathogenic
1047873	GRCh37/hg19 7q31.2-31.33(chr7:116297277-126370694)	Pathogenic
1322091	NM_005763.4(AASS):c.2100T>G (p.Tyr700Ter)	Pathogenic
145985	GRCh38/hg38 7q31.1-31.33(chr7:114142477-125840381)x1	Pathogenic
1527383	GRCh37/hg19 7q22.3-32.1(chr7:106984287-128949489)	Pathogenic
154454	GRCh38/hg38 7q31.32-32.1(chr7:122018122-128907727)x1	Pathogenic
1950187	NM_005763.4(AASS):c.709G>T (p.Glu237Ter)	Pathogenic
2425417	NC_000007.13:g.(?121738484)(121773780_?)del	Pathogenic
253455	GRCh37/hg19 7q31.1-32.1(chr7:111613396-127897316)x1	Pathogenic
2682543	NC_000007.13:g.(121733213_121738503)(121784304?)del	Pathogenic
3062992	GRCh37/hg19 7q31.31-33(chr7:120582003-137699953)x1	Pathogenic
3063765	NM_005763.4(AASS):c.904dup (p.Tyr302fs)	Pathogenic
3629522	NC_000007.13:g.(121758685_121766428)(121784304?)del	Pathogenic
442834	GRCh37/hg19 7p22.3-q36.3(chr7:43361-159119707)x3	Pathogenic
5209	NM_005763.4(AASS):c.1601_1609del (p.Cys534_Glu537delinsTer)	Pathogenic
563422	GRCh37/hg19 7q22.1-36.3(chr7:98693388-159119707)x3	Pathogenic
687212	GRCh37/hg19 7q31.32-32.2(chr7:121480906-129389003)x1	Pathogenic
687530	GRCh37/hg19 7q31.32(chr7:121734181-121803684)x1	Pathogenic
688682	GRCh37/hg19 7q31.32(chr7:121734934-121803684)x1	Pathogenic
815014	GRCh37/hg19 7q22.3-31.32(chr7:106617406-123217914)x1	Pathogenic
100646	NM_005763.4(AASS):c.194G>A (p.Arg65Gln)	Likely pathogenic
1048521	NM_005763.4(AASS):c.3G>A (p.Met1Ile)	Likely pathogenic
1048522	NM_005763.4(AASS):c.395G>A (p.Arg132His)	Likely pathogenic
1334629	NM_005763.4(AASS):c.2196dup (p.Ala733fs)	Likely pathogenic
1878391	NC_000007.13:g.(121733213_121738503)_(121773796_121784214)del	Likely pathogenic
2663547	NM_005763.4(AASS):c.2428C>T (p.Gln810Ter)	Likely pathogenic

SpliceAI

3207 predictions. Top by Δscore:

Variant	Effect	Δscore
7:122076604:TCACC:T	acceptor_loss	1.0000
7:122076605:CACCT:C	acceptor_loss	1.0000
7:122076607:CCTGG:C	acceptor_loss	1.0000
7:122077833:CTTA:C	donor_loss	1.0000
7:122077836:A:AC	donor_gain	1.0000
7:122077836:AC:A	donor_gain	1.0000
7:122077837:C:CC	donor_gain	1.0000
7:122077837:CC:C	donor_gain	1.0000
7:122077837:CCA:C	donor_gain	1.0000
7:122077837:CCAT:C	donor_gain	1.0000
7:122078011:GGAC:G	acceptor_gain	1.0000
7:122078012:GAC:G	acceptor_gain	1.0000
7:122078014:CCT:C	acceptor_gain	1.0000
7:122078015:C:CC	acceptor_gain	1.0000
7:122078015:C:T	acceptor_gain	1.0000
7:122078016:T:C	acceptor_gain	1.0000
7:122078016:T:TC	acceptor_gain	1.0000
7:122078022:CAAA:C	acceptor_gain	1.0000
7:122078023:A:T	acceptor_gain	1.0000
7:122078025:A:C	acceptor_gain	1.0000
7:122078874:TCATG:T	donor_gain	1.0000
7:122079591:GCCTA:G	donor_loss	1.0000
7:122079592:CCTA:C	donor_loss	1.0000
7:122079593:CTACC:C	donor_loss	1.0000
7:122079594:TACC:T	donor_loss	1.0000
7:122079595:A:AC	donor_gain	1.0000
7:122079595:ACC:A	donor_loss	1.0000
7:122079596:C:CA	donor_loss	1.0000
7:122079596:C:CC	donor_gain	1.0000
7:122079710:TTTC:T	acceptor_loss	1.0000

AlphaMissense

6074 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:122126397:A:C	F150L	1.000
7:122126397:A:T	F150L	1.000
7:122126399:A:G	F150L	1.000
7:122113151:A:C	F415L	0.999
7:122113151:A:T	F415L	0.999
7:122113153:A:G	F415L	0.999
7:122126383:C:T	G155D	0.999
7:122126436:C:A	E137D	0.999
7:122126436:C:G	E137D	0.999
7:122126437:T:A	E137V	0.999
7:122129421:G:C	F109L	0.999
7:122129421:G:T	F109L	0.999
7:122129423:A:G	F109L	0.999
7:122129469:T:A	K93N	0.999
7:122129469:T:G	K93N	0.999
7:122129470:T:A	K93I	0.999
7:122133610:C:A	R39S	0.999
7:122133610:C:G	R39S	0.999
7:122133611:C:A	R39M	0.999
7:122133611:C:G	R39T	0.999
7:122133621:A:G	W36R	0.999
7:122133621:A:T	W36R	0.999
7:122113165:C:G	A411P	0.998
7:122113185:G:T	P404Q	0.998
7:122118398:C:G	R199P	0.998
7:122118413:G:T	A194D	0.998
7:122126395:C:T	G151E	0.998
7:122126437:T:G	E137A	0.998
7:122129406:T:A	K114N	0.998
7:122129406:T:G	K114N	0.998

dbSNP variants (sampled 300 via entrez): RS1000032495 (7:122080872 A>G), RS1000048265 (7:122144446 C>T), RS1000059960 (7:122086515 A>T), RS1000133155 (7:122086150 A>C,T), RS1000201333 (7:122138861 C>T), RS1000204170 (7:122122697 G>GT), RS1000242950 (7:122093305 G>A,T), RS1000327210 (7:122099755 A>G,T), RS1000327887 (7:122119983 T>A,G), RS1000352882 (7:122145377 G>T), RS1000401106 (7:122099213 C>G,T), RS1000478734 (7:122106688 T>A), RS1000538169 (7:122131661 C>T), RS1000569948 (7:122137466 G>A), RS1000587480 (7:122101254 A>G)

Disease associations

OMIM: gene MIM:605113 | disease phenotypes: MIM:238700, MIM:268700

GenCC curated gene-disease

Disease	Classification	Inheritance
hyperlysinemia	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
hyperlysinemia	Definitive	AR

Mondo (3): hyperlysinemia (MONDO:0009388), microcephaly (MONDO:0001149), saccharopinuria (MONDO:0010005)

Orphanet (2): Hyperlysinemia (Orphanet:2203), Saccharopinuria (Orphanet:3124)

HPO phenotypes

78 total (30 of 78 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000218	High palate
HP:0000252	Microcephaly
HP:0000319	Smooth philtrum
HP:0000457	Depressed nasal ridge
HP:0000486	Strabismus
HP:0000601	Hypotelorism
HP:0000609	Optic nerve hypoplasia
HP:0000708	Atypical behavior
HP:0000736	Short attention span
HP:0000750	Delayed speech and language development
HP:0000752	Hyperactivity
HP:0001083	Ectopia lentis
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001256	Mild intellectual disability
HP:0001263	Global developmental delay
HP:0001264	Spastic diplegia
HP:0001268	Mental deterioration
HP:0001285	Spastic tetraparesis
HP:0001310	Dysmetria
HP:0001337	Tremor
HP:0001348	Brisk reflexes
HP:0001363	Craniosynostosis
HP:0001507	Growth abnormality
HP:0001508	Failure to thrive
HP:0001903	Anemia
HP:0001987	Hyperammonemia
HP:0001999	Abnormal facial shape

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST012221_3	Opioid dependence (time to event)	3.000000e-07

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500
C537218	Saccharopinuria (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

54 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases abundance	4
perfluorooctane sulfonic acid	decreases expression	4
Benzo(a)pyrene	affects methylation, decreases expression, increases methylation	4
Estradiol	affects cotreatment, decreases expression	3
Valproic Acid	affects expression, decreases expression, increases expression	3
perfluorooctanoic acid	decreases expression	2
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	2
Acetaminophen	decreases expression	2
Gold	decreases expression, affects binding	2
Phenylmercuric Acetate	decreases expression, affects cotreatment	2
Tetrachlorodibenzodioxin	decreases expression	2
Cyclosporine	decreases expression	2
aristolochic acid I	decreases expression	1
lasiocarpine	decreases expression	1
methyleugenol	decreases expression	1
triphenyl phosphate	affects expression	1
propionaldehyde	increases expression	1
bisphenol A	decreases expression	1
chlortoluron	decreases expression	1
deoxynivalenol	decreases expression	1
cobaltous chloride	decreases expression	1
nickel sulfate	decreases expression	1
nivalenol	decreases expression	1
avobenzone	increases expression	1
CGP 52608	affects binding, increases reaction	1
perfluoro-n-nonanoic acid	decreases expression	1
monomethylarsonous acid	decreases expression	1
abrine	increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
LDN 193189	decreases expression, affects cotreatment	1

Clinical trials (associated diseases)

17 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT05518188	PHASE1/PHASE2	RECRUITING	Melpida: Recombinant Adeno-associated Virus (serotype 9) Encoding a Codon Optimized Human AP4M1 Transgene (hAP4M1opt)
NCT00001639	Not specified	COMPLETED	Evaluation of Patients With Unresolved Chromosome Abnormalities
NCT01151462	Not specified	WITHDRAWN	Postnatal HCMV Infection in Very Preterm Infants. Implications, Morbidity, Growth and Neurodevelopmental Outcomes.
NCT01565005	Not specified	COMPLETED	Microcephaly Genetic Deficiency in Neural Progenitors
NCT02510170	Not specified	COMPLETED	Fetal and Maternal Head Circumference During Pregnancy in Israeli Population
NCT02741882	Not specified	COMPLETED	Zika and Microcephaly: Case-control Study
NCT02943304	Not specified	COMPLETED	Neurodevelopment Outcome of Newborns Exposed to Zika Virus (ZIKV) in Utero
NCT03255369	Not specified	UNKNOWN	Vertical Exposure to Zika Virus and Its Consequences for Child Neurodevelopment (ZIKVIRUSIFF)
NCT03325946	Not specified	RECRUITING	The FBRI VTC Neuromotor Research Clinic
NCT03330600	Not specified	COMPLETED	Efficacy of Aquatic Physiotherapy in Children With Microcephaly by Zika Virus Congenital Syndrome
NCT03548779	Not specified	COMPLETED	North Carolina Genomic Evaluation by Next-generation Exome Sequencing, 2
NCT03651687	Not specified	COMPLETED	Guangzhou Surveillance and Clinical Study in Microcephaly (GSCSM)
NCT03922594	Not specified	TERMINATED	Surveillance of Zika-related Microcephaly in Sub-Saharan Africa and Asia
NCT04816175	Not specified	COMPLETED	Intensive Therapy for Children With Microcephaly, Hyperkinetic Movements, or Global Developmental Delay
NCT05322980	Not specified	COMPLETED	Summary of Infants Weighing 500 Grams or Less
NCT06019182	Not specified	RECRUITING	MEHMO Natural History and Biomarkers
NCT06566066	Not specified	RECRUITING	Register for Patients With Thyroid Hormone Resistance.