ALDH4A1

aldehyde dehydrogenase 4 family member A1, the group of Aldehyde dehydrogenases|MicroRNA protein coding host genes

Basic information

Region (hg38): 1:18871430-18902724

Previous symbols: [ "ALDH4" ]

Links

ENSG00000159423 ∙ NCBI:8659 ∙ OMIM:606811 ∙ HGNC:406 ∙ Uniprot:P30038 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• hyperprolinemia type 2 (Definitive), mode of inheritance: AR
• hyperprolinemia type 2 (Strong), mode of inheritance: AR
• hyperprolinemia type 2 (Limited), mode of inheritance: AR
• hyperprolinemia type 2 (Supportive), mode of inheritance: AR
• hyperprolinemia type 2 (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Hyperprolinemia, type II	AR	General	The clinical relevance of the condition is unclear	Biochemical; Neurologic	9700195; 10780262

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the ALDH4A1 gene.

• Hyperprolinemia_type_2 (238 variants)
• not_specified (58 variants)
• not_provided (47 variants)
• ALDH4A1-related_disorder (13 variants)
• Intellectual_disability (7 variants)
• Seizure (2 variants)
• See_cases (1 variants)
• MHC_class_II_deficiency_1 (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the ALDH4A1 gene is commonly pathogenic or not. These statistics are base on transcript: NM_000003748.4. Only rare variants are included in the table.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Effect	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			5	80	2	87
missense		2	116	19		137
nonsense	1	3	1			5
start loss		1				1
frameshift	2	13	2			17
splice donor/acceptor (+/-2bp)		6				6
Total	3	25	124	99	2

Highest pathogenic variant AF is 0.000144994

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
ALDH4A1	protein_coding	protein_coding	ENST00000375341	15	31350

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.0000137	0.998	125673	0	75	125748	0.000298

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-0.0467	357	355	1.01	0.0000234	3596
Missense in Polyphen		144	153.95	0.93538		1479
Synonymous	0.376	150	156	0.962	0.0000115	1118
Loss of Function	2.75	13	28.9	0.449	0.00000142	323

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000974	0.000972
Ashkenazi Jewish	0.0000992	0.0000992
East Asian	0.000330	0.000326
Finnish	0.0000464	0.0000462
European (Non-Finnish)	0.000349	0.000334
Middle Eastern	0.000330	0.000326
South Asian	0.000231	0.000229
Other	0.000333	0.000326

dbNSFP

Source: dbNSFP

• Function: 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. {ECO:0000269|PubMed:22516612}.
• Pathway: Alanine, aspartate and glutamate metabolism - Homo sapiens (human);Arginine and proline metabolism - Homo sapiens (human);2-Hydroxyglutric Aciduria (D And L Form);Hyperornithinemia with gyrate atrophy (HOGA);Creatine deficiency, guanidinoacetate methyltransferase deficiency;L-arginine:glycine amidinotransferase deficiency;Hyperornithinemia-hyperammonemia-homocitrullinuria [HHH-syndrome];Guanidinoacetate Methyltransferase Deficiency (GAMT Deficiency);Homocarnosinosis;Hyperinsulinism-Hyperammonemia Syndrome;Succinic semialdehyde dehydrogenase deficiency;Prolinemia Type II;Prolidase Deficiency (PD);Arginine and Proline Metabolism;4-Hydroxybutyric Aciduria/Succinic Semialdehyde Dehydrogenase Deficiency;Hyperprolinemia Type I;Hyperprolinemia Type II;Ornithine Aminotransferase Deficiency (OAT Deficiency);Arginine: Glycine Amidinotransferase Deficiency (AGAT Deficiency);Glutamate Metabolism;Proline catabolism;Glutamate Glutamine metabolism;Histidine, lysine, phenylalanine, tyrosine, proline and tryptophan catabolism;Metabolism of amino acids and derivatives;Metabolism;proline degradation;4-hydroxyproline degradation;Urea cycle and metabolism of arginine, proline, glutamate, aspartate and asparagine;Glyoxylate metabolism and glycine degradation;Arginine Proline metabolism (Consensus)

Recessive Scores

• pRec: 0.213

Intolerance Scores

• loftool: 0.915
• rvis_EVS: 0.21
• rvis_percentile_EVS: 67.52

Haploinsufficiency Scores

• pHI: 0.722
• hipred: Y
• hipred_score: 0.637
• ghis: 0.401

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.939

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

• Gene name: Aldh4a1

Gene ontology

• Biological process: proline metabolic process;proline catabolic process;proline catabolic process to glutamate;4-hydroxyproline catabolic process;electron transport chain;glyoxylate metabolic process
• Cellular component: mitochondrial matrix
• Molecular function: 1-pyrroline-5-carboxylate dehydrogenase activity;aldehyde dehydrogenase (NAD) activity;electron transfer activity;identical protein binding