ALDH4A1

Summary

ALDH4A1 (aldehyde dehydrogenase 4 family member A1, HGNC:406) is a protein-coding gene on chromosome 1p36.13, encoding Delta-1-pyrroline-5-carboxylate dehydrogenase, mitochondrial (P30038). Irreversible conversion of delta-1-pyrroline-5-carboxylate (P5C), derived either from proline or ornithine, to glutamate.

This protein belongs to the aldehyde dehydrogenase family of proteins. This enzyme is a mitochondrial matrix NAD-dependent dehydrogenase which catalyzes the second step of the proline degradation pathway, converting pyrroline-5-carboxylate to glutamate. Deficiency of this enzyme is associated with type II hyperprolinemia, an autosomal recessive disorder characterized by accumulation of delta-1-pyrroline-5-carboxylate (P5C) and proline. Alternatively spliced transcript variants encoding different isoforms have been identified for this gene.

Source: NCBI Gene 8659 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hyperprolinemia type 2 (Definitive, ClinGen)
• GWAS associations: 3
• Clinical variants (ClinVar): 389 total — 6 pathogenic, 18 likely-pathogenic
• Phenotypes (HPO): 56
• Druggable target: yes
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_003748

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:406
Approved symbol	ALDH4A1
Name	aldehyde dehydrogenase 4 family member A1
Location	1p36.13
Locus type	gene with protein product
Status	Approved
Aliases	P5CDh
Ensembl gene	ENSG00000159423
Ensembl biotype	protein_coding
OMIM	606811
Entrez	8659

Gene structure

Transcript identifiers

Ensembl transcripts: 24 — 22 protein_coding, 1 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000290597, ENST00000375341, ENST00000432718, ENST00000454547, ENST00000538309, ENST00000538839, ENST00000870350, ENST00000870351, ENST00000870352, ENST00000870353, ENST00000870354, ENST00000870355, ENST00000870356, ENST00000870357, ENST00000870358, ENST00000870359, ENST00000870360, ENST00000870361, ENST00000924552, ENST00000924553, ENST00000924554, ENST00000924555, ENST00000924556, ENST00000971517

RefSeq mRNA: 4 — MANE Select: NM_003748 NM_001161504, NM_001319218, NM_003748, NM_170726

CCDS: CCDS188, CCDS53272, CCDS81273

Canonical transcript exons

ENST00000375341 — 15 exons

Exon	Start	End
ENSE00001906223	18902462	18902555
ENSE00003467881	18889362	18889454
ENSE00003469755	18875382	18875503
ENSE00003481052	18885473	18885628
ENSE00003496017	18874463	18874581
ENSE00003514751	18877208	18877255
ENSE00003521564	18886464	18886511
ENSE00003557914	18876315	18876467
ENSE00003558878	18877416	18877612
ENSE00003575887	18883124	18883198
ENSE00003600909	18881700	18881887
ENSE00003620310	18879300	18879373
ENSE00003633838	18883279	18883428
ENSE00003663540	18890012	18890105
ENSE00003847692	18871430	18872957

Expression profiles

Bgee: expression breadth ubiquitous, 248 present calls, max score 98.96.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 18.8894 / max 621.0394, expressed in 1804 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
10613	14.2964	1780
10614	3.4443	1549
10616	0.9371	339
10615	0.2031	66
10612	0.0085	2

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right lobe of liver	UBERON:0001114	98.96	gold quality
liver	UBERON:0002107	97.47	gold quality
adult mammalian kidney	UBERON:0000082	97.38	gold quality
nephron tubule	UBERON:0001231	93.82	gold quality
hindlimb stylopod muscle	UBERON:0004252	93.44	gold quality
gastrocnemius	UBERON:0001388	93.34	gold quality
putamen	UBERON:0001874	93.04	gold quality
kidney epithelium	UBERON:0004819	92.83	gold quality
kidney	UBERON:0002113	92.78	gold quality
amygdala	UBERON:0001876	92.73	gold quality
caudate nucleus	UBERON:0001873	92.62	gold quality
muscle of leg	UBERON:0001383	92.22	gold quality
right frontal lobe	UBERON:0002810	91.97	gold quality
cingulate cortex	UBERON:0003027	91.59	gold quality
anterior cingulate cortex	UBERON:0009835	91.56	gold quality
nucleus accumbens	UBERON:0001882	91.41	gold quality
cortex of kidney	UBERON:0001225	90.87	gold quality
middle frontal gyrus	UBERON:0002702	90.76	gold quality
metanephric glomerulus	UBERON:0004736	90.74	gold quality
esophagus mucosa	UBERON:0002469	90.55	gold quality
renal glomerulus	UBERON:0000074	90.53	gold quality
muscle organ	UBERON:0001630	90.40	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	90.30	gold quality
endometrium epithelium	UBERON:0004811	90.01	gold quality
triceps brachii	UBERON:0001509	89.46	silver quality
apex of heart	UBERON:0002098	89.35	gold quality
lower esophagus mucosa	UBERON:0035834	89.10	gold quality
substantia nigra	UBERON:0002038	88.94	gold quality
gluteal muscle	UBERON:0002000	88.63	silver quality
heart left ventricle	UBERON:0002084	88.58	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	10.98

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): TP53

miRNA regulators (miRDB)

56 targeting ALDH4A1, 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-4481	100.00	66.42	1669
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4745-5P	99.98	65.95	1028
HSA-MIR-4715-3P	99.98	66.03	670
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-3910	99.95	71.13	2227
HSA-MIR-3681-3P	99.88	70.46	2254
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-4319	99.76	69.83	2586
HSA-MIR-6745	99.74	65.33	1321
HSA-MIR-6766-5P	99.68	67.70	2325
HSA-MIR-6715B-5P	99.64	69.63	1420
HSA-MIR-762	99.58	66.61	1994
HSA-MIR-4269	99.55	69.89	1373
HSA-MIR-7106-5P	99.53	67.47	3574
HSA-MIR-4498	99.47	67.42	2360
HSA-MIR-766-5P	99.47	67.91	2225
HSA-MIR-363-5P	99.46	64.51	1015
HSA-MIR-642A-3P	99.23	67.67	1258
HSA-MIR-642B-3P	99.23	67.67	1258
HSA-MIR-544B	99.18	67.41	1632
HSA-MIR-4254	99.11	65.15	1315
HSA-MIR-4651	99.06	67.57	2002
HSA-MIR-5001-5P	99.05	66.76	1972
HSA-MIR-1207-3P	98.99	66.22	1532
HSA-MIR-3154	98.94	66.55	1455
HSA-MIR-608	98.93	67.83	2013

Functional genomics

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

Literature-anchored findings (GeneRIF, showing 7)

• ALDH4 is a p53-inducible gene with a protective role in cellular stresses (PMID:14986171)
• ALDH4 is transcriptionally induced by p53. (PMID:14986171)
• the impact of the hyperprolinemia-associated mutation of Ser352 to Leu on the structure and catalytic properties of the P5CDH (PMID:22516612)
• ALDH4A1 expression levels are elevated in postmortem brains of patients with schizophrenia and are associated with genetic variants in enzymes related to proline metabolism. (PMID:32065947)
• ALDH4A1 is an atherosclerosis auto-antigen targeted by protective antibodies. (PMID:33268892)
• Genetic variation in ALDH4A1 is associated with muscle health over the lifespan and across species. (PMID:35470798)
• Atherosclerotic Autoantigen ALDH4A1 as a Novel Immunological Indicator for Plaque Erosion in Patients with ST Segment Elevated Myocardial Infarction. (PMID:38109905)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	aldh4a1	ENSDARG00000038207
mus_musculus	Aldh4a1	ENSMUSG00000028737
rattus_norvegicus	Aldh4a1	ENSRNOG00000071265
drosophila_melanogaster	P5CDh1	FBGN0037138
drosophila_melanogaster	P5CDh2	FBGN0053092
caenorhabditis_elegans		WBGENE00000112

Paralogs (17): ALDH3B1 (ENSG00000006534), ALDH3A2 (ENSG00000072210), ALDH3A1 (ENSG00000108602), ALDH2 (ENSG00000111275), ALDH5A1 (ENSG00000112294), ALDH8A1 (ENSG00000118514), ALDH6A1 (ENSG00000119711), ALDH1A2 (ENSG00000128918), ALDH3B2 (ENSG00000132746), ALDH1L2 (ENSG00000136010), ALDH1B1 (ENSG00000137124), ALDH9A1 (ENSG00000143149), ALDH1L1 (ENSG00000144908), ALDH16A1 (ENSG00000161618), ALDH7A1 (ENSG00000164904), ALDH1A1 (ENSG00000165092), ALDH1A3 (ENSG00000184254)

Protein

Protein identifiers

Delta-1-pyrroline-5-carboxylate dehydrogenase, mitochondrial — P30038 (reviewed: P30038)

Alternative names: Aldehyde dehydrogenase family 4 member A1, L-glutamate gamma-semialdehyde dehydrogenase

All UniProt accessions (2): P30038, A0A024RAC7

UniProt curated annotations — full annotation on UniProt →

Function. Irreversible conversion of delta-1-pyrroline-5-carboxylate (P5C), derived either from proline or ornithine, to glutamate. This is a necessary step in the pathway interconnecting the urea and tricarboxylic acid cycles. The preferred substrate is glutamic gamma-semialdehyde, other substrates include succinic, glutaric and adipic semialdehydes.

Subunit / interactions. Homodimer.

Subcellular location. Mitochondrion matrix.

Tissue specificity. Highest expression is found in liver followed by skeletal muscle, kidney, heart, brain, placenta, lung and pancreas.

Disease relevance. Hyperprolinemia 2 (HYRPRO2) [MIM:239510] An inborn error of proline metabolism resulting in elevated plasma levels of proline and delta-1-pyrroline-5-carboxylate (P5C). The condition is considered to be benign, but affected individuals can exhibit neurological manifestations that vary in severity. Clinical signs include seizures, intellectual deficit and mild developmental delay. The disease is caused by variants affecting the gene represented in this entry.

Pathway. Amino-acid degradation; L-proline degradation into L-glutamate; L-glutamate from L-proline: step 2/2.

Similarity. Belongs to the aldehyde dehydrogenase family.

Isoforms (3)

UniProt ID	Names	Canonical?
P30038-1	1	yes
P30038-2	2
P30038-3	3

RefSeq proteins (4): NP_001154976, NP_001306147, NP_003739, NP_733844 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR005931	P5CDH/ALDH4A1	Family
IPR015590	Aldehyde_DH_dom	Domain
IPR016160	Ald_DH_CS_CYS	Conserved_site
IPR016161	Ald_DH/histidinol_DH	Homologous_superfamily
IPR016162	Ald_DH_N	Homologous_superfamily
IPR016163	Ald_DH_C	Homologous_superfamily
IPR029510	Ald_DH_CS_GLU	Conserved_site

Pfam: PF00171

Enzyme classification (BRENDA):

• EC 1.2.1.88 — L-glutamate gamma-semialdehyde dehydrogenase (BRENDA: 40 organisms, 54 substrates, 88 inhibitors, 75 Km, 35 kcat entries)

Substrate kinetics (BRENDA)

16 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
1-PYRROLINE-5-CARBOXYLATE	0.037–2	21
NAD+	0.02–103	16
L-GLUTAMATE 5-SEMIALDEHYDE	0.12–97	9
NADP+	0.0095–3.066	9
GLUTARIC SEMIALDEHYDE	0.032–0.48	7
2-AMINOADIPIC SEMIALDEHYDE	0.173–0.211	2
3-METHOXYBENZALDEHYDE	0.5	1
4-METHOXYBENZALDEHYDE	0.25	1
ACETALDEHYDE	1	1
BENZALDEHYDE	0.5	1
D-GLUCOSE	0.133	1
D-GLYCERALDEHYDE 3-PHOSPHATE	1.86	1
FORMALDEHYDE	0.76	1
GLYOXYLIC ACID	1	1
INDOL-3-ACETALDEHYDE	0.2	1

Catalyzed reactions (Rhea), 1 shown:

• L-glutamate 5-semialdehyde + NAD(+) + H2O = L-glutamate + NADH + 2 H(+) (RHEA:30235)

UniProt features (99 total): modified residue 23, strand 23, helix 23, sequence conflict 8, binding site 5, turn 5, sequence variant 4, active site 2, splice variant 2, transit peptide 1, chain 1, mutagenesis site 1, site 1

Structure

Experimental structures (PDB)

6 structures.

PDB	Method	Resolution (Å)
8RKR	X-RAY DIFFRACTION	1.2
4OE5	X-RAY DIFFRACTION	1.95
3V9H	X-RAY DIFFRACTION	2.4
3V9G	X-RAY DIFFRACTION	2.5
8RKQ	X-RAY DIFFRACTION	2.6
3V9I	X-RAY DIFFRACTION	2.85

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P30038-F1	96.22	0.95

Functional residue map

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

Catalytic / active sites (3): 314 (proton acceptor); 348 (nucleophile); 211 (transition state stabilizer)

Ligand- & substrate-binding residues (5): 208; 233; 286–290; 447; 513

Post-translational modifications (23): 31, 44, 52, 93, 93, 99, 99, 114, 114, 130, 130, 175, 175, 318, 347, 365, 376, 395, 462, 509 …

Mutagenesis-validated functional residues (1):

Position	Phenotype
352	reduced affinity for nad. no effect on enzyme activity.

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-389661	Glyoxylate metabolism and glycine degradation
R-HSA-70688	Proline catabolism
R-HSA-1430728	Metabolism
R-HSA-71291	Metabolism of amino acids and derivatives

MSigDB gene sets: 290 (showing top): MODULE_93, ELVIDGE_HYPOXIA_DN, GNF2_GSTM1, GOBP_ALPHA_AMINO_ACID_METABOLIC_PROCESS, GNF2_HPN, GOBP_GLUTAMATE_METABOLIC_PROCESS, GOBP_MODIFIED_AMINO_ACID_CATABOLIC_PROCESS, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_UP, GOBP_GLUTAMINE_FAMILY_AMINO_ACID_METABOLIC_PROCESS, GOBP_DICARBOXYLIC_ACID_METABOLIC_PROCESS, MODULE_66, WANG_ESOPHAGUS_CANCER_VS_NORMAL_DN, LI_WILMS_TUMOR_VS_FETAL_KIDNEY_1_UP, MODULE_272

GO Biological Process (4): L-proline metabolic process (GO:0006560), L-proline catabolic process (GO:0006562), obsolete L-proline catabolic process to L-glutamate (GO:0010133), trans-4-hydroxy-L-proline catabolic process (GO:0019470)

GO Molecular Function (7): L-glutamate gamma-semialdehyde dehydrogenase activity (GO:0003842), aldehyde dehydrogenase (NAD+) activity (GO:0004029), electron transfer activity (GO:0009055), identical protein binding (GO:0042802), protein binding (GO:0005515), oxidoreductase activity (GO:0016491), oxidoreductase activity, acting on the aldehyde or oxo group of donors, NAD or NADP as acceptor (GO:0016620)

GO Cellular Component (3): 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	2
Metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
L-amino acid catabolic process	2
cytoplasm	2
L-amino acid metabolic process	1
proteinogenic amino acid metabolic process	1
L-proline metabolic process	1
proteinogenic amino acid catabolic process	1
modified amino acid catabolic process	1
non-proteinogenic amino acid catabolic process	1
oxidoreductase activity, acting on the aldehyde or oxo group of donors, NAD or NADP as acceptor	1
aldehyde dehydrogenase [NAD(P)+] activity	1
molecular_function	1
protein binding	1
binding	1
catalytic activity	1
oxidoreductase activity, acting on the aldehyde or oxo group of donors	1
intracellular membrane-bounded organelle	1
mitochondrion	1
intracellular organelle lumen	1
cellular anatomical structure	1

Protein interactions and networks

STRING

3454 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ALDH4A1	PRODH	O43272	983
ALDH4A1	PRODH	O43272	981
ALDH4A1	ALDH18A1	P54886	899
ALDH4A1	OAT	P04181	777
ALDH4A1	PYCR1	P32322	768
ALDH4A1	PYCR2	Q96C36	684
ALDH4A1	PYCR3	Q53H96	674
ALDH4A1	ARG2	P78540	658
ALDH4A1	PRODH2	Q9UF12	603
ALDH4A1	IVD	P26440	572
ALDH4A1	GLS2	Q9UI32	543
ALDH4A1	GLUD1	P00367	529
ALDH4A1	GLUL	P15104	516
ALDH4A1	SERPIND1	P05546	497
ALDH4A1	ASS1	P00966	491

IntAct

52 interactions, top by confidence:

A	B	Type	Score
EXOC1	EXOC5	psi-mi:“MI:0914”(association)	0.730
LRRC46	TBP	psi-mi:“MI:0914”(association)	0.640
RBBP4	ALDH4A1	psi-mi:“MI:0915”(physical association)	0.560
ALDH4A1	ALDH4A1	psi-mi:“MI:0407”(direct interaction)	0.560
ARRB1	SAG	psi-mi:“MI:0914”(association)	0.530
STK16	UNC119B	psi-mi:“MI:0914”(association)	0.530
LPAR1	TMEM223	psi-mi:“MI:0914”(association)	0.530
SKA2	VSIG8	psi-mi:“MI:0914”(association)	0.530
ARG1	ALDH4A1	psi-mi:“MI:0915”(physical association)	0.370
TMEM184A	NRDC	psi-mi:“MI:0914”(association)	0.350
ARRB1	SAG	psi-mi:“MI:0914”(association)	0.350
MAPT	SHTN1	psi-mi:“MI:0914”(association)	0.350
OR2A4	A2ML1	psi-mi:“MI:0914”(association)	0.350
FFAR1	SLC12A8	psi-mi:“MI:0914”(association)	0.350
CCR1	UBA6	psi-mi:“MI:0914”(association)	0.350
MRM2	VWA8	psi-mi:“MI:0914”(association)	0.350
QRSL1	VWA8	psi-mi:“MI:0914”(association)	0.350
YARS2	VWA8	psi-mi:“MI:0914”(association)	0.350
ACSM5	VWA8	psi-mi:“MI:0914”(association)	0.350
AK4	VWA8	psi-mi:“MI:0914”(association)	0.350
FAHD1	VWA8	psi-mi:“MI:0914”(association)	0.350
GPR45	VWA8	psi-mi:“MI:0914”(association)	0.350
MALSU1	GTPBP10	psi-mi:“MI:0914”(association)	0.350
PYCR1	POTEF	psi-mi:“MI:0914”(association)	0.350

BioGRID (117): AHCY (Co-fractionation), ALDH4A1 (Co-fractionation), ALDH4A1 (Co-fractionation), ALDH4A1 (Co-fractionation), ALDH4A1 (Co-fractionation), ALDH4A1 (Co-fractionation), ALDH4A1 (Co-fractionation), ALDH4A1 (Co-fractionation), ALDH4A1 (Co-fractionation), ALDH4A1 (Co-fractionation), ALDH4A1 (Co-fractionation), ALDH4A1 (Co-fractionation), ALDH4A1 (Co-fractionation), ENO1 (Co-fractionation), ENO3 (Co-fractionation)

ESM2 similar proteins: A7YWE4, O74766, O75891, P07275, P0C2X9, P25795, P28037, P30038, P46562, P49419, P51649, P51650, P54889, P78568, P83401, Q02252, Q02253, Q07536, Q0WM29, Q141D3, Q1GV29, Q29HB2, Q2KJC9, Q2SKP1, Q3MSM3, Q3MSM4, Q3SY69, Q41247, Q54RA2, Q5RFM9, Q64057, Q6A2H0, Q6A2H1, Q6A2H2, Q6JQN1, Q7KW39, Q7QC84, Q7SY23, Q802W2, Q8BWF0

Diamond homologs: A0A7W3RCJ3, A0R909, A3M365, A4IJP9, A4VKC2, A4XPI6, A5IVY0, A6QK44, A6U4T5, A6VEI4, A6ZR27, A7GKJ4, A7X6R7, A8F9T1, A8Z3F5, A9VRG6, B0V944, B2HV80, B2JS88, B2TCJ9, B6ECN9, B7GFV3, B7GYG4, B7H4V1, B7HSW8, B7I896, B7IUW8, B7JM99, B7V5R4, B9J1L9, C1EV77, C3K3D2, C3L546, C3PBP4, C5D4J5, D4GP41, D5E1S7, O52485, O74187, P07275

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	6
Likely pathogenic	18
Uncertain significance	155
Likely benign	119
Benign	31

Top pathogenic / likely-pathogenic (24)

Variant ID	HGVS	Classification
1526027	NM_003748.4(ALDH4A1):c.72del (p.Arg23_Trp24insTer)	Pathogenic
2424756	NC_000001.10:g.(?19199339)(19201095_?)del	Pathogenic
3633307	NM_003748.4(ALDH4A1):c.451C>T (p.Gln151Ter)	Pathogenic
3705082	NM_003748.4(ALDH4A1):c.960_964del (p.His321fs)	Pathogenic
4770797	NM_003748.4(ALDH4A1):c.200del (p.Val67fs)	Pathogenic
980392	GRCh37/hg19 1p36.21-36.12(chr1:16041431-21295864)x1	Pathogenic
1690556	NM_003748.4(ALDH4A1):c.641del (p.Ala214fs)	Likely pathogenic
1809608	NM_003748.4(ALDH4A1):c.363_370dup (p.Arg124fs)	Likely pathogenic
2627894	NM_003748.4(ALDH4A1):c.240C>G (p.Tyr80Ter)	Likely pathogenic
3337793	NM_003748.4(ALDH4A1):c.194del (p.Pro65fs)	Likely pathogenic
3574718	NM_003748.4(ALDH4A1):c.1580-2A>G	Likely pathogenic
3574732	NM_003748.4(ALDH4A1):c.1333A>T (p.Lys445Ter)	Likely pathogenic
3574737	NM_003748.4(ALDH4A1):c.1152dup (p.Gly385fs)	Likely pathogenic
3574741	NM_003748.4(ALDH4A1):c.1137delC (p.Pro380fs)	Likely pathogenic
3574746	NM_003748.4(ALDH4A1):c.1057dup (p.Arg353fs)	Likely pathogenic
3574753	NM_003748.4(ALDH4A1):c.689_696dup (p.Lys233fs)	Likely pathogenic
3574758	NM_003748.4(ALDH4A1):c.551dup (p.Pro185fs)	Likely pathogenic
3574763	NM_003748.4(ALDH4A1):c.453+1G>A	Likely pathogenic
3574765	NM_003748.4(ALDH4A1):c.356del (p.Lys119fs)	Likely pathogenic
3574770	NM_003748.4(ALDH4A1):c.250-2A>G	Likely pathogenic
3574776	NM_003748.4(ALDH4A1):c.19_34dup (p.Leu12fs)	Likely pathogenic
3655571	NM_003748.4(ALDH4A1):c.1461-2A>G	Likely pathogenic
4004	NM_003748.4(ALDH4A1):c.21del (p.Leu8fs)	Likely pathogenic
571282	NM_003748.4(ALDH4A1):c.298-1G>C	Likely pathogenic

SpliceAI

3082 predictions. Top by Δscore:

Variant	Effect	Δscore
1:18874461:A:AT	donor_loss	1.0000
1:18874462:C:A	donor_loss	1.0000
1:18874577:CGTCC:C	acceptor_gain	1.0000
1:18874580:CC:C	acceptor_gain	1.0000
1:18874581:CC:C	acceptor_gain	1.0000
1:18875379:CACT:C	donor_loss	1.0000
1:18875380:A:AC	donor_gain	1.0000
1:18875380:AC:A	donor_loss	1.0000
1:18875381:C:CA	donor_gain	1.0000
1:18875381:C:G	donor_loss	1.0000
1:18875381:CTT:C	donor_gain	1.0000
1:18875381:CTTAT:C	donor_gain	1.0000
1:18875384:A:AC	donor_gain	1.0000
1:18875384:AT:A	donor_gain	1.0000
1:18875384:ATC:A	donor_gain	1.0000
1:18875385:T:C	donor_gain	1.0000
1:18875417:G:C	donor_gain	1.0000
1:18875501:CTC:C	acceptor_gain	1.0000
1:18875502:TC:T	acceptor_gain	1.0000
1:18875503:CC:C	acceptor_gain	1.0000
1:18875504:C:CC	acceptor_gain	1.0000
1:18875504:C:CG	acceptor_loss	1.0000
1:18875505:T:C	acceptor_loss	1.0000
1:18876316:T:TA	donor_gain	1.0000
1:18876317:C:A	donor_gain	1.0000
1:18876331:T:TA	donor_gain	1.0000
1:18876336:AGGGT:A	donor_gain	1.0000
1:18876340:T:TA	donor_gain	1.0000
1:18876463:AAGGA:A	acceptor_gain	1.0000
1:18876464:AGGA:A	acceptor_gain	1.0000

AlphaMissense

3667 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:18883169:G:C	N211K	1.000
1:18883169:G:T	N211K	1.000
1:18872916:A:G	W541R	0.998
1:18872916:A:T	W541R	0.998
1:18874482:A:C	F520L	0.998
1:18874482:A:T	F520L	0.998
1:18874484:A:G	F520L	0.998
1:18883166:G:C	F212L	0.998
1:18883166:G:T	F212L	0.998
1:18883168:A:G	F212L	0.998
1:18883172:A:C	F210L	0.998
1:18883172:A:T	F210L	0.998
1:18883174:A:G	F210L	0.998
1:18875409:A:G	L478P	0.997
1:18875495:G:C	F449L	0.997
1:18875495:G:T	F449L	0.997
1:18875497:A:G	F449L	0.997
1:18877514:T:C	K347E	0.997
1:18881714:G:C	F284L	0.997
1:18881714:G:T	F284L	0.997
1:18881716:A:G	F284L	0.997
1:18875401:C:G	A481P	0.996
1:18877495:C:G	R353P	0.996
1:18877512:C:A	K347N	0.996
1:18877512:C:G	K347N	0.996
1:18881872:A:G	W232R	0.996
1:18881872:A:T	W232R	0.996
1:18885580:A:G	W116R	0.996
1:18885580:A:T	W116R	0.996
1:18872957:C:T	G527E	0.995

dbSNP variants (sampled 300 via entrez): RS1000052413 (1:18895662 C>T), RS1000056158 (1:18902035 G>A), RS1000265722 (1:18871131 T>A,C), RS1000340732 (1:18880284 G>C), RS1000356598 (1:18881654 G>A,T), RS1000537948 (1:18885396 T>C,G), RS1000598010 (1:18872432 G>A), RS1000686385 (1:18880108 A>G,T), RS1000846517 (1:18890384 A>G), RS1000911517 (1:18875336 C>G), RS1001063558 (1:18901763 T>A), RS1001228721 (1:18876859 T>G), RS1001312170 (1:18895859 G>A), RS1001330977 (1:18875962 A>C), RS1001404588 (1:18885877 T>C)

Disease associations

OMIM: gene MIM:606811 | disease phenotypes: MIM:239510, MIM:209920

GenCC curated gene-disease

Disease	Classification	Inheritance
hyperprolinemia type 2	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
hyperprolinemia type 2	Definitive	AR

Mondo (3): hyperprolinemia type 2 (MONDO:0009401), intellectual disability (MONDO:0001071), MHC class II deficiency 1 (MONDO:0971005)

Orphanet (2): Hyperprolinemia type 2 (Orphanet:79101), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

56 total (30 of 56 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000083	Renal insufficiency
HP:0000496	Abnormality of eye movement
HP:0000511	Vertical supranuclear gaze palsy
HP:0000597	Ophthalmoparesis
HP:0000708	Atypical behavior
HP:0000716	Depression
HP:0000718	Aggressive behavior
HP:0000729	Autistic behavior
HP:0000736	Short attention span
HP:0000738	Hallucinations
HP:0000739	Anxiety
HP:0000750	Delayed speech and language development
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001263	Global developmental delay
HP:0001284	Areflexia
HP:0001289	Confusion
HP:0001298	Encephalopathy
HP:0001345	Psychotic mentation
HP:0002014	Diarrhea
HP:0002015	Dysphagia
HP:0002027	Abdominal pain
HP:0002133	Status epilepticus
HP:0002154	Hyperglycinemia
HP:0002197	Generalized-onset seizure
HP:0002317	Unsteady gait
HP:0002360	Sleep disturbance
HP:0002373	Febrile seizure (within the age range of 3 months to 6 years)
HP:0002490	Increased CSF lactate

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST001961_1	Anorexia nervosa	9.000000e-06
GCST002775_6	Alzheimer’s disease (survival time)	3.000000e-06
GCST009391_1966	Metabolite levels	2.000000e-07

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0000714	survival time
EFO:0010541	trimethylamine-N-oxide measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
C538385	Hyperprolinemia type 2 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL3414418 (SINGLE PROTEIN), CHEMBL3542434 (PROTEIN FAMILY)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Cyclosporine	decreases expression	4
bisphenol A	increases expression, affects cotreatment, decreases expression	3
Benzo(a)pyrene	affects methylation, decreases expression, decreases methylation	3
bisphenol F	increases expression, affects cotreatment	2
bisphenol S	increases expression, affects cotreatment	2
Dexamethasone	increases expression, affects cotreatment	2
Aflatoxin B1	affects expression, decreases expression	2
aristolochic acid I	increases expression	1
apocarotenal	decreases expression	1
methyleugenol	decreases expression	1
propionaldehyde	increases expression	1
nobiletin	decreases expression, decreases reaction	1
sodium arsenate	decreases expression, decreases reaction	1
hesperetin	affects binding	1
sulforaphane	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
1-benzylimidazole	decreases expression	1
periodate-oxidized adenosine	affects expression	1
aflatoxin B2	decreases methylation	1
4-aminophenylarsenoxide	affects binding, decreases reaction	1
di-n-butylphosphoric acid	affects expression	1
glycidamide	decreases expression	1
perfluorooctane sulfonic acid	decreases expression	1
CGP 52608	affects binding, increases reaction	1
perfluoro-n-nonanoic acid	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
nutlin 3	affects cotreatment, increases secretion	1
bisphenol B	increases expression	1
jinfukang	affects cotreatment, increases expression	1
LDN 193189	affects cotreatment, increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3419570	Binding	Effect on human ALDH4A1 at 20 uM preincubated for 2 mins with NAD+ followed by aldehyde substrate addition	Characterization of two distinct structural classes of selective aldehyde dehydrogenase 1A1 inhibitors. — J Med Chem

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_D2I2	Abcam Raji ALDH4A1 KO	Cancer cell line	Male
CVCL_UQ13	Abcam Jurkat ALDH4A1 KO	Cancer cell line	Male
CVCL_WQ97	Abcam K-562 ALDH4A1 KO	Cancer cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT03479476	PHASE2/PHASE3	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome
NCT02616796	PHASE1/PHASE2	COMPLETED	Effects of Social Gaze Training on Brain and Behavior in Fragile X Syndrome
NCT06860672	EARLY_PHASE1	RECRUITING	Clinical Trial of the Dual Vector Base Editor for the Treatment of the CHD3-R1025W Mutation
NCT00597948	Not specified	COMPLETED	Healthy Lifestyles for People With Intellectual Disabilities
NCT01087320	Not specified	RECRUITING	Genome Medical Sequencing for Gene Discovery
NCT01652963	Not specified	UNKNOWN	Picture-based Computerised Assessment and Training of Cognitive Behaviour Therapy Skills
NCT01695395	Not specified	COMPLETED	Mental Health Care Provision for Adults With Intellectual Disability and a Mental Disorder
NCT01867554	Not specified	COMPLETED	Research and Characterization of New Genes Involved in Intellectual Disability
NCT01915381	Not specified	COMPLETED	Improving Adherence Healthy Lifestyle With a Smartphone Application Based on Adults With Intellectual Disabilities
NCT01988623	Not specified	COMPLETED	Pivotal Response Treatment for Individuals With Intellectual Disabilities
NCT02099773	Not specified	COMPLETED	Support Staff-client Interactions With Augmentative and Alternative Communication
NCT02136849	Not specified	COMPLETED	Inter-regional Project of the Great Western Exploration Approach for Exome Molecular Causes Severe Intellectual Disability Isolated or Syndromic
NCT02225041	Not specified	COMPLETED	Sedation Strategy and Cognitive Outcome After Critical Illness in Early Childhood
NCT02414438	Not specified	COMPLETED	Establishing the Clinical Utility of First StepDx PLUS and NextStepDx PLUS Study
NCT02451761	Not specified	COMPLETED	Apparently Balanced Chromosomal Translocation/ Next-generation Sequencing/ Intellectual Disability
NCT02461420	Not specified	ACTIVE_NOT_RECRUITING	Mapping the Genotype, Phenotype, and Natural History of Phelan-McDermid Syndrome
NCT02461459	Not specified	ACTIVE_NOT_RECRUITING	Autism Spectrum Disorder (ASD) and Intellectual Disability (ID) Determinants in Tuberous Sclerosis Complex (TSC)
NCT02486081	Not specified	COMPLETED	Development and Application-Smart Football for Movement Evaluation and Training in the Special Education Population
NCT02504502	Not specified	COMPLETED	Enhancing Genomic Laboratory Reports to Enhance Communication and Empower Patients
NCT02513277	Not specified	COMPLETED	Diabetes Screening & Prevention for People With Learning (Intellectual) Disabilities:STOP Diabetes Study
NCT02561754	Not specified	COMPLETED	Weight Management for Adolescents With IDD
NCT02591446	Not specified	COMPLETED	Transcranial Magnetic Stimulation Studies in Autism Spectrum Disorders
NCT02714868	Not specified	COMPLETED	Evaluation of Project TEAM (Teens Making Environmental and Activity Modifications)
NCT02721394	Not specified	UNKNOWN	FCT With Young Children With ID in the UK: A Feasibility Project V.1
NCT02746614	Not specified	COMPLETED	Psychomotor Therapy Effects in Adaptive Behavior and Motor Proficiency in Intellectual Disability
NCT02836405	Not specified	COMPLETED	TMS for the Investigation of Brain Plasticity in Autism Spectrum Disorders