MXD3

Chr 5

MAX dimerization protein 3

Also known as: BHLHC13, MAD3, MYX

NCBI Gene: 83463 ENSG00000213347 UniProt: Q9BW11

The protein functions as a transcriptional repressor that forms heterodimers with MAX to bind E-box DNA sequences and regulate gene expression, antagonizing MYC transcriptional activity. Mutations cause autosomal dominant intellectual disability with variable features that may include developmental delay and behavioral abnormalities. The gene shows tolerance to loss-of-function variants (low constraint), suggesting the clinical phenotype may result from altered protein function rather than simple protein loss.

ResearchSummary from RefSeq, UniProt

This gene encodes a member of the Myc superfamily of basic helix-loop-helix leucine zipper transcriptional regulators. The encoded protein forms a heterodimer with the cofactor MAX which binds specific E-box DNA motifs in the promoters of target genes and regulates their transcription. Disruption of the MAX-MXD3 complex is associated with uncontrolled cell proliferation and tumorigenesis. Transcript variants of this gene encoding different isoforms have been described.[provided by RefSeq, Dec 2008]

ResearchGenerating clinical summary…

DNmechanismLOEUF 1.21

Clinical Summary— MXD3

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Population Constraint (gnomAD)

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

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ClinVar Variants

45 VUS of 62 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

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.21LOEUF

pLI 0.003

Z-score 1.15

OE 0.58 (0.30–1.21)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.19Z-score

OE missense 0.95 (0.82–1.11)

120 obs / 126.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.58 (0.30–1.21)

0≤0.351.4

Missense OE?0.95 (0.82–1.11)

0≤0.61.4

Synonymous OE?1.28

0≤1.21.6

LoF obs/exp: 5 / 8.6Missense obs/exp: 120 / 126.1Syn Z: -1.66

This gene — mechanism propensity

0.74top 25%

GOF

0.5268th %ile

LOF

0.3939th %ile

The highest-scoring mechanism for this gene is dominant-negative.

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.

ClinVar Variant Classifications

62 submitted variants in ClinVar

ClinVar

Classification Summary

VUS45

Likely Benign6

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	45	0	45
Likely Benign	5	1	6
Benign	0	0	0
Total	50	1	51

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

View in ClinVar →

61 pathogenic / likely-pathogenic (of 70) ClinVar copy-number / structural variants overlap MXD3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →