ALKBH5

Chr 17

alkB homolog 5, RNA demethylase

Also known as: ABH5, OFOXD, OFOXD1

NCBI Gene: 54890 ENSG00000091542 UniProt: Q6P6C2

The ALKBH5 protein is a dioxygenase that specifically removes N6-methyladenosine (m6A) modifications from RNA, thereby regulating mRNA processing, translation, and export. Mutations in this gene cause autosomal recessive intellectual disability with delayed speech and language development. This gene is highly constrained against loss-of-function variants (pLI 0.95, LOEUF 0.34), suggesting that complete loss of protein function is poorly tolerated.

ResearchSummary from RefSeq, UniProt

Enables mRNA N6-methyladenosine dioxygenase activity and molecular condensate scaffold activity. Involved in membraneless organelle assembly; post-transcriptional regulation of gene expression; and response to hypoxia. Acts upstream of or within regulation of mRNA export from nucleus and regulation of mRNA processing. Located in Golgi apparatus; cytosol; and nuclear speck. Is active in paraspeckles. [provided by Alliance of Genome Resources, Jul 2025]

ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.34

Clinical Summary— ALKBH5

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.95). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

39 VUS of 50 total submissions

Explore recent and relevant literature in Research Assistant →

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.34LOEUF

pLI 0.950

Z-score 3.20

OE 0.07 (0.03–0.34)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

2.56Z-score

OE missense 0.54 (0.47–0.62)

131 obs / 243.5 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.07 (0.03–0.34)

0≤0.351.4

Missense OE?0.54 (0.47–0.62)

0≤0.61.4

Synonymous OE?1.51

0≤1.21.6

LoF obs/exp: 1 / 13.8Missense obs/exp: 131 / 243.5Syn Z: -3.97

This gene — mechanism propensity

0.2199th %ile

GOF

0.2796th %ile

LOF

0.80top 5%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · LOEUF 0.34

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

50 submitted variants in ClinVar

ClinVar

Classification Summary

VUS39

Likely Benign2

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Synonymous	Total
Pathogenic	0	0	0
Likely Pathogenic	0	0	0
VUS	39	0	39
Likely Benign	0	2	2
Benign	0	0	0
Total	39	2	41

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

116 pathogenic / likely-pathogenic (of 122) ClinVar copy-number / structural variants overlap ALKBH5 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →