ASH1L

Chr 1AD

ASH1 like histone lysine methyltransferase

Also known as: ASH1, ASH1L1, KMT2H, MRD52

NCBI Gene: 55870 ENSG00000116539 UniProt: Q9NR48 OMIM: 607999

The protein is a trithorax group transcriptional activator that localizes to nuclear speckles and cell-cell tight junctions, containing AT hooks, a SET domain, PHD-finger motif, and bromodomain. Loss-of-function mutations cause autosomal dominant intellectual developmental disorder (intellectual developmental disorder, autosomal dominant 52). The gene is highly intolerant to loss-of-function variants, consistent with haploinsufficiency as the pathogenic mechanism.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene encodes a member of the trithorax group of transcriptional activators. The protein contains four AT hooks, a SET domain, a PHD-finger motif, and a bromodomain. It is localized to many small speckles in the nucleus, and also to cell-cell tight junctions. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.061 OMIM phenotype

Clinical Summary— ASH1L

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Gene-Disease Validity (ClinGen)

syndromic complex neurodevelopmental disorder · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

103 unique Pathogenic / Likely Pathogenic· 633 VUS of 974 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.06LOEUF

pLI 1.000

Z-score 10.13

OE 0.02 (0.01–0.06)

Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?

3.47Z-score

OE missense 0.75 (0.72–0.79)

1179 obs / 1565.3 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.02 (0.01–0.06)

0≤0.351.4

Missense OE?0.75 (0.72–0.79)

0≤0.61.4

Synonymous OE?0.93

0≤1.21.6

LoF obs/exp: 3 / 125.3Missense obs/exp: 1179 / 1565.3Syn Z: 1.24

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongASH1L-related intellectual disabilityOTHERAD

This gene — mechanism propensity

0.17100th %ile

GOF

0.1899th %ile

LOF

0.89top 5%

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

LOFprediction above median · 1 literature citation · 92% of P/LP variants are LoF · LOEUF 0.06 · ClinGen HI: Sufficient evidence for dosage pathogenicity

Literature Evidence

LOFWhereas KMT2C or ASH1L haploinsufficiency results in a predominantly neurodevelopmental phenotype with occasional physical anomalies, KMT5B mutations cause an overgrowth syndrome with intellectual disability.1

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

References

1.PMID 29276005 ↗

ClinVar Variant Classifications

974 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic65

Likely Pathogenic38

VUS633

Likely Benign145

Benign21

Conflicting21

Pathogenic

Likely Pathogenic

633

VUS

145

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	61	3	1	0	65
Likely Pathogenic	34	4	0	0	38
VUS	8	611	6	8	633
Likely Benign	1	82	6	56	145
Benign	0	8	3	10	21
Conflicting	—				21
Total	104	708	16	74	923

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

View in ClinVar →

15 pathogenic / likely-pathogenic (of 31) ClinVar copy-number / structural variants overlap ASH1L — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →