ALDH1L1

Chr 3

aldehyde dehydrogenase 1 family member L1

Also known as: 10-FTHFDH, 10-fTHF, FDH, FTHFD

NCBI Gene: 10840 ENSG00000144908 UniProt: O75891 OMIM: 600249

This cytosolic enzyme catalyzes the NADP-dependent conversion of 10-formyltetrahydrofolate to tetrahydrofolate and carbon dioxide, functioning in folate metabolism. Mutations cause autosomal recessive developmental delay, seizures, and brain malformations with onset in infancy or early childhood. The gene is not highly constrained against loss-of-function variants, consistent with its recessive inheritance pattern.

OMIM ResearchSummary from RefSeq, UniProt

The protein encoded by this gene catalyzes the conversion of 10-formyltetrahydrofolate, nicotinamide adenine dinucleotide phosphate (NADP+), and water to tetrahydrofolate, NADPH, and carbon dioxide. The encoded protein belongs to the aldehyde dehydrogenase family. Loss of function or expression of this gene is associated with decreased apoptosis, increased cell motility, and cancer progression. There is an antisense transcript that overlaps on the opposite strand with this gene locus. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jun 2012]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.78

Clinical Summary— ALDH1L1

⚡

Population Constraint (gnomAD)

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

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.78LOEUF

pLI 0.000

Z-score 2.76

OE 0.56 (0.40–0.78)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.60Z-score

OE missense 0.93 (0.86–1.00)

512 obs / 552.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.56 (0.40–0.78)

0≤0.351.4

Missense OE?0.93 (0.86–1.00)

0≤0.61.4

Synonymous OE?1.02

0≤1.21.6

LoF obs/exp: 25 / 45.0Missense obs/exp: 512 / 552.0Syn Z: -0.29

This gene — mechanism propensity

0.76top 25%

GOF

0.78top 25%

LOF

0.2190th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

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