ALDH4A1

Chr 1AR

aldehyde dehydrogenase 4 family member A1

Also known as: ALDH4, P5CD, P5CDh

NCBI Gene: 8659 ENSG00000159423 UniProt: P30038 OMIM: 606811

This mitochondrial enzyme converts pyrroline-5-carboxylate to glutamate in the proline degradation pathway, serving as a critical link between the urea and tricarboxylic acid cycles. Mutations cause autosomal recessive type II hyperprolinemia, characterized by accumulation of pyrroline-5-carboxylate and proline. The gene shows low constraint to loss-of-function variants, consistent with the recessive inheritance pattern.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Hyperprolinemia, type IIMIM #239510

UniProtHyperprolinemia 2

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · hyperprolinemia type 2 · AR · ClinGen 2020

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype), though the gene is not strongly LoF-constrained in the population — weigh truncating variants against that tolerance.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.71

LOEUF

LOF

Mechanism· G2P

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.71LOEUF

pLI 0.000

Z-score 2.75

OE 0.45 (0.29–0.71)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

-0.05Z-score

OE missense 1.01 (0.92–1.10)

357 obs / 354.5 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.45 (0.29–0.71)

0≤0.351.4

Missense OE?1.01 (0.92–1.10)

0≤0.61.4

Synonymous OE?0.96

0≤1.21.6

LoF obs/exp: 13 / 28.9Missense obs/exp: 357 / 354.5Syn Z: 0.38

Background carrier burden — how many people carry a rare variant somewhere in ALDH4A1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 57

793 rare PASS variants

Rare truncating (LoF)

1 in 740

137 rare PASS variants

Rare synonymous (reference)

1 in 75

345 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for ALDH4A1. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 83	1 in 820
South Asian	~43k	1 in 58	1 in 450
Remaining (unassigned)	~30k	1 in 61	1 in 710
European (Finnish)	~27k	1 in 240	1 in 680
Admixed American	~22k	1 in 46	1 in 1,200
African / African American	~21k	1 in 67	1 in 510
East Asian	~20k	1 in 67	1 in 870
Ashkenazi Jewish	~13k	1 in 370	none seen
Middle Eastern	~2,884	1 in 51	1 in 570

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 14 of 15 coding exons well covered in gnomAD exomes; exon 1 marginal. Genomes: all 15.? see exons ↓