ALDH4A1

Chr 1AR

aldehyde dehydrogenase 4 family member A1

Also known as: ALDH4, P5CD, P5CDh

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.

OMIMResearchSummary from RefSeq, OMIM, UniProt
LOFmechanismARLOEUF 0.711 OMIM phenotype
Clinical SummaryALDH4A1
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Gene-Disease Validity (ClinGen)
hyperprolinemia type 2 · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

Tolerant — LoF & missense variants common in population
LoF Constraint
0.71LOEUF
pLI 0.000
Z-score 2.75
OE 0.45 (0.290.71)
Tolerant

Typical tolerance to LoF variation

Missense Constraint
-0.05Z-score
OE missense 1.01 (0.921.10)
357 obs / 354.5 exp
Tolerant

Tolerant to missense variation

Observed / Expected Ratios
LoF OE0.45 (0.290.71)
00.351.4
Missense OE1.01 (0.921.10)
00.61.4
Synonymous OE0.96
01.21.6
LoF obs/exp: 13 / 28.9Missense obs/exp: 357 / 354.5Syn Z: 0.38
Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗
definitiveALDH4A1-related hyperprolinemiaLOFAR

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

DN
0.7327th %ile
GOF
0.6540th %ile
LOF
0.3164th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

0 submitted variants in ClinVar

Protein Context — Lollipop Plot

ALDH4A1 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

3D Protein StructureAlphaFold

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

No active trials found for this gene.

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Clinical Literature
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