MAML2

Chr 11

mastermind like transcriptional coactivator 2

Also known as: MAM-3, MAM2, MAM3, MLL-MAML2

NCBI Gene: 84441 ENSG00000184384 UniProt: Q8IZL2

The protein encoded by this gene is a member of the Mastermind-like family of proteins. All family members are proline and glutamine-rich, and contain a conserved basic domain that binds the ankyrin repeat domain of the intracellular domain of the Notch receptors (ICN1-4) in their N-terminus, and a transcriptional activation domain in their C-terminus. This protein binds to an extended groove that is formed by the interaction of CBF1, Suppressor of Hairless, LAG-1 (CSL) with ICN, and positively regulates Notch signaling. High levels of expression of this gene have been observed in several B cell-derived lymphomas. Translocations resulting in fusion proteins with both CRTC1 and CRTC3 have been implicated in the development of mucoepidermoid carcinomas, while a translocation event with CXCR4 has been linked with chronic lymphocytic leukemia (CLL). Copy number variation in the polyglutamine tract has been observed. [provided by RefSeq, Jan 2015]

Research

ResearchGenerating clinical summary…

Clinical highlights

Gene–disease validity (ClinGen)

Refuted · congenital heart disease · UD · ClinGen 2024

evidence has disproved this relationship

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

102

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.23

LOEUF· LoF intol.

LOF

Mechanism· predicted

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?

0.23LOEUF

pLI 1.000

Z-score 5.90

OE 0.12 (0.06–0.23)

Highly constrained

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

Missense Constraint?

0.45Z-score

OE missense 0.95 (0.89–1.02)

584 obs / 615.4 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.12 (0.06–0.23)

0≤0.351.4

Missense OE?0.95 (0.89–1.02)

0≤0.61.4

Synonymous OE?1.06

0≤1.21.6

LoF obs/exp: 6 / 51.9Missense obs/exp: 584 / 615.4Syn Z: -0.75

Background carrier burden — how many people carry a rare variant somewhere in MAML2?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 38

1,478 rare PASS variants

Rare truncating (LoF)

1 in 470

80 rare PASS variants

Rare synonymous (reference)

1 in 81

604 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for MAML2. 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 48	1 in 670
South Asian	~43k	1 in 43	1 in 910
Remaining (unassigned)	~30k	1 in 29	1 in 4,800
European (Finnish)	~27k	1 in 110	≈ 1 in 7,800
Admixed American	~22k	1 in 39	none seen
African / African American	~21k	1 in 42	1 in 2,800
East Asian	~20k	1 in 36	1 in 240
Ashkenazi Jewish	~13k	1 in 260	≈ 1 in 6,500
Middle Eastern	~2,884	1 in 39	none seen

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): All 5 coding exons well covered in gnomAD exomes and genomes.? see exons ↓