DMXL2

Chr 15ADAR

Dmx like 2

Also known as: DEE81, DFNA71, EIEE81, PEPNS, RC3

NCBI Gene: 23312 ENSG00000104093 UniProt: Q8TDJ6 OMIM: 612186

This protein contains 12 WD domains and serves as a scaffold protein for synaptic vesicle components, functioning as a key controller of neuronal and endocrine homeostatic processes. Mutations cause developmental and epileptic encephalopathy 81, polyendocrine-polyneuropathy syndrome, and autosomal dominant deafness, with both autosomal dominant and recessive inheritance patterns reported. The gene is highly constrained against loss-of-function variants (pLI ~1.0, LOEUF 0.158), indicating that even single functional copies are critical for normal development.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a protein with 12 WD domains. Proteins with WD domains are involved in many functions including participation in signal transduction pathways. Participation of the encoded protein in regulation of the Notch signaling pathway has been demonstrated in vitro using several human cell lines (PMID:20810660). A gene encoding a similar protein is located on chromosome 5. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2011]

OMIM ResearchGenerating clinical summary…

LOFmechanismAD/ARLOEUF 0.163 OMIM phenotypes

Clinical Summary— DMXL2

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Gene-Disease Validity (ClinGen)

nonsyndromic genetic hearing loss · ADLimited

Limited evidence — not for standalone diagnostic reporting

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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

66 unique Pathogenic / Likely Pathogenic· 850 VUS of 1966 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.16LOEUF

pLI 1.000

Z-score 10.06

OE 0.10 (0.07–0.16)

Highly constrained

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

Missense Constraint?

2.37Z-score

OE missense 0.83 (0.79–0.87)

1297 obs / 1560.0 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.10 (0.07–0.16)

0≤0.351.4

Missense OE?0.83 (0.79–0.87)

0≤0.61.4

Synonymous OE?1.03

0≤1.21.6

LoF obs/exp: 15 / 146.4Missense obs/exp: 1297 / 1560.0Syn Z: -0.61

This gene — mechanism propensity

0.3495th %ile

GOF

0.2597th %ile

LOF

0.80top 5%

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

LOFprediction above median · 91% of P/LP variants are LoF · LOEUF 0.16

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

1966 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic51

Likely Pathogenic15

VUS850

Likely Benign889

Benign102

Conflicting31

Pathogenic

Likely Pathogenic

850

VUS

889

Likely Benign

102

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	46	2	3	0	51
Likely Pathogenic	14	0	1	0	15
VUS	6	806	36	2	850
Likely Benign	2	21	335	531	889
Benign	0	15	68	19	102
Conflicting	—				31
Total	68	844	443	552	1,938

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

View in ClinVar →

21 pathogenic / likely-pathogenic (of 34) ClinVar copy-number / structural variants overlap DMXL2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →