ALDH4A1

protein-coding

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

Gene summary

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. [provided by RefSeq, Jun 2009]

Previous symbols:

ALDH4

MANE transcript

NM_003748.4

Inheritance

ClinVar variants

P:32U:133B:111

Top phenotype

Hyperprolinemia, type II

gnomAD constraint

pLI —, LoF o/e 0.45

Max pathogenic AF

—

Genomic locus

chr1:18,871,430-18,902,724

External References & Databases

Ensembl (ENSG00000159423)

Transcript & Mutation Effects

hg38 • Region Span ~31.3 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hyperprolinemia type 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009401

Submitter: Labcorp Genetics (formerly Invitae)

hyperprolinemia type 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009401

Submitter: PanelApp Australia

hyperprolinemia type 2DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009401

Submitter: ClinGen

The relationship between ALDH4A1 and hyperprolinemia type II, an autosomal recessive disorder of proline metabolism, was evaluated using the ClinGen Clinical Validity Framework as of October 21, 2020. ALDH4A1 encodes delta1-pyrroline-5-carboxylic acid dehydrogenase (P5CDh), a mitochondrial matrix protein that catalyzes the conversion of L-glutamate-γ-semialdehyde, the hydrolysis product of delta1-pyrroline-5-carboxylate (P5C), to L-glutamate. Individuals with hyperprolinemia type II have elevated P5C levels, about 10-20 times normal levels of plasma proline, and positive o-aminobenzaldehyde reaction in urine (due to presence of delta-pyrroline products). Some patients with hyperprolinemia have seizures and intellectual disability, and Vitamin B6 may be deficient. Biallelic variants in ALDH4A1 in individuals with hyperprolinemia type II were first reported in 1998 by Geraghty et al (PMID 9700195). One other paper has been published since then (Motte et al, 2019, PMID: 31884946). In total, data from 4 patients who are homozygous or compound heterozygous for ALDH4A1 variants were scored, including 5 unique variants (two missense, two frameshift, one splice variant). One of these variants, c.1560dup, was found to be homozygous in 7 individuals (a father and 6 affected children), and heterozygous in an unaffected sibling, in a branch of a large Irish traveler family (Flynn et al, 1989, PMID 2624476). Another individual with hyperprolinemia type II was reported to be homozygous for a missense variant, p.Pro16Leu, in ALDH4A1, but this variant may be benign based on the allele frequency and results of functional studies (PMID 9700195). This gene-disease relationship is supported by the biochemical function of P5CDh which is consistent with the biochemical differences observed in individuals with hyperprolinemia type II (Strecker, 1960, PMID 13835167; Valle et al, 1974, PMID 4369405; Hu et al, 1996, PMID: 8621661). P5C, which accumulates in individuals with hyperprolinemia type II, has been shown to react with pyridoxal phosphate, providing an explanation for low or low normal vitamin B6 levels in patients with hyperprolinemia II, a possible cause for seizures in affected individuals, and leading to the suggestion that individuals with hyperprolinemia type II may benefit from treatment with Vitamin B6 (Farrant et al, 2001, PMID 11134058; Hassel et al, 2019, PMID 30930802), although not all patients seem to show improvement (van den Ven et al, 2014, PMID 24173411). In addition to the biochemical function of P5CDh, the gene-disease relationship is also supported by the finding of elevated proline in a Drosophila model with a C-terminal deletion of a P5CDh orthologue (He and DiMario, 2011, PMID 21168532). In summary, there is definitive evidence to support this gene-disease relationship. This clinical validity classification was approved by the ClinGen Aminoacidopathy Gene Curation Expert Panel.

hyperprolinemia type 2DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009401

Submitter: G2P

hyperprolinemia type 2LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0009401

Submitter: Ambry Genetics

hyperprolinemia type 2SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009401

Submitter: Orphanet

Clinical Genomic Database (CGD)

Hyperprolinemia, type IIAR

Manifestation: Biochemical; Neurologic

Intervention: General

Rationale: The clinical relevance of the condition is unclear

Refs: 9700195; 10780262

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ALDH4A1 variants in ClinVar

9 Conditions Cataloged

Hyperprolinemia type 2Total: 262

not specifiedTotal: 75

not providedTotal: 47

ALDH4A1-related disorderTotal: 14

Intellectual disabilityTotal: 7

EpilepsyTotal: 2

SeizureTotal: 2

See casesTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_003748.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			6 clinvar	89 clinvar	1 clinvar	96
missense		3 clinvar	122 clinvar	21 clinvar		146
nonsense	1 clinvar	4 clinvar				5
start loss		1 clinvar				1
frameshift	3 clinvar	13 clinvar	2 clinvar			18
splice donor/acceptor (+/-2bp)		7 clinvar	3 clinvar			10
Total	4	28	133	110	1	276

Highest pathogenic variant AF is 0.00014499355

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 57 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_003748.4	RefSeq	NP_003739.2	15	MANE Select
ENST00000375341.8	Ensembl	ENSP00000364490.3	15	MANE Select
NM_001161504.2	RefSeq	NP_001154976.1	13	Standard
NM_001319218.2	RefSeq	NP_001306147.1	14	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

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

Biological Process

proline metabolic process
proline catabolic process
proline catabolic process to glutamate
4-hydroxyproline catabolic process
electron transport chain

Molecular Function

1-pyrroline-5-carboxylate dehydrogenase activity
aldehyde dehydrogenase (NAD) activity
electron transfer activity
identical protein binding

Cellular Component

mitochondrial matrix

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000375341
Coding exons: 15
Length: 31350
Individuals with no LoFs: 125673
Homozygous LoFs: 0
Heterozygous LoFs: 75
Defined: 125748
p: 0.000298

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.0467	357	355	1.01	0.0000234	3596
Missense (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

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00074	0.00074	rare
Latino/Admixed American	0.00023	0.00023	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.00033	0.00033	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00035	0.00033	rare
South Asian	0.00023	0.00023	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

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}.;

Recessive Scores

pRec: 0.213

Intolerance Scores

LoFtool: 0.915
RVIS EVS: 0.21
RVIS percentile EVS: 67.52

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.939

Gene Damage Prediction

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