MAL2

Chr 8

mal, T cell differentiation protein 2

NCBI Gene: 114569 ENSG00000147676 UniProt: Q969L2 OMIM: 609684

The protein is a transmembrane component of lipid rafts that is required for transcytosis, the intracellular transport pathway that delivers proteins and cargo from the basolateral to apical cell surface in polarized cells. Mutations cause autosomal recessive congenital diarrhea with protein-losing enteropathy, presenting in early infancy with severe diarrhea and failure to thrive due to intestinal epithelial transport defects. This gene shows relatively low constraint to loss-of-function variants.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a multispan transmembrane protein belonging to the MAL proteolipid family. The protein is a component of lipid rafts and, in polarized cells, it primarily localizes to endosomal structures beneath the apical membrane. It is required for transcytosis, an intracellular transport pathway used to deliver membrane-bound proteins and exogenous cargos from the basolateral to the apical surface. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.10

Clinical Summary— MAL2

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Population Constraint (gnomAD)

Low constraint (pLI 0.14) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

11 VUS of 22 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.10LOEUF

pLI 0.137

Z-score 1.43

OE 0.35 (0.14–1.10)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.50Z-score

OE missense 0.84 (0.69–1.03)

67 obs / 79.4 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.35 (0.14–1.10)

0≤0.351.4

Missense OE?0.84 (0.69–1.03)

0≤0.61.4

Synonymous OE?0.98

0≤1.21.6

LoF obs/exp: 2 / 5.7Missense obs/exp: 67 / 79.4Syn Z: 0.09

This gene — mechanism propensity

0.79top 25%

GOF

0.85top 5%

LOF

0.1993th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median

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

22 submitted variants in ClinVar

ClinVar

Classification Summary

VUS11

VUS

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Total
Pathogenic	0	0
Likely Pathogenic	0	0
VUS	11	11
Likely Benign	0	0
Benign	0	0
Total	11	11

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

View in ClinVar →

55 pathogenic / likely-pathogenic (of 64) ClinVar copy-number / structural variants overlap MAL2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →