MLXIPL

Chr 7

MLX interacting protein like

Also known as: CHREBP, MIO, MONDOB, WBSCR14, WS-bHLH, bHLHd14

NCBI Gene: 51085 ENSG00000009950 UniProt: Q9NP71 OMIM: 605678

This gene encodes a glucose-responsive transcription factor that regulates fatty acid synthesis and glycolysis, serving as a key determinant of systemic insulin sensitivity and glucose homeostasis. MLXIPL is deleted in Williams-Beuren syndrome, a multisystem developmental disorder with autosomal dominant inheritance caused by contiguous gene deletions at chromosome 7q11.23. The gene shows moderate constraint against loss-of-function variants (LOEUF 0.47), suggesting some intolerance to complete loss of function.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a basic helix-loop-helix leucine zipper transcription factor of the Myc/Max/Mad superfamily. This protein forms a heterodimeric complex and binds and activates, in a glucose-dependent manner, carbohydrate response element (ChoRE) motifs in the promoters of triglyceride synthesis genes. The gene is deleted in Williams-Beuren syndrome, a multisystem developmental disorder caused by the deletion of contiguous genes at chromosome 7q11.23. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2015]

OMIM ResearchGenerating clinical summary…

DNmechanismLOEUF 0.47

Clinical Summary— MLXIPL

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.27) despite low pLI — interpret in context.

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ClinVar Variants

120 VUS of 211 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.47LOEUF

pLI 0.048

Z-score 3.90

OE 0.27 (0.16–0.47)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.23Z-score

OE missense 0.84 (0.77–0.91)

391 obs / 465.8 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.27 (0.16–0.47)

0≤0.351.4

Missense OE?0.84 (0.77–0.91)

0≤0.61.4

Synonymous OE?0.92

0≤1.21.6

LoF obs/exp: 9 / 33.2Missense obs/exp: 391 / 465.8Syn Z: 0.89

This gene — mechanism propensity

0.6647th %ile

GOF

0.4480th %ile

LOF

0.4627th %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

211 submitted variants in ClinVar

ClinVar

Classification Summary

VUS120

Likely Benign48

Benign17

120

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0	0
Likely Pathogenic	0	0	0	0	0
VUS	1	119	0	0	120
Likely Benign	1	19	4	24	48
Benign	0	7	4	6	17
Total	2	145	8	30	185

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

View in ClinVar →

165 pathogenic / likely-pathogenic (of 170) ClinVar copy-number / structural variants overlap MLXIPL — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →