MAP1B

Chr 5AD

microtubule associated protein 1B

Also known as: DFNA83, FUTSCH, MAP5, PPP1R102, PVNH9

NCBI Gene: 4131 ENSG00000131711 UniProt: P46821 OMIM: 157129

MAP1B encodes a microtubule-associated protein that facilitates tubulin modification and is required for proper microtubule dynamics during neuronal differentiation and neurite extension. Mutations cause autosomal dominant deafness and periventricular nodular heterotopia, a brain malformation affecting neuronal migration. This gene is extremely intolerant to loss-of-function variants, reflecting its critical role in nervous system development.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

MultiplemechanismADLOEUF 0.132 OMIM phenotypes

Clinical Summary— MAP1B

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Gene-Disease Validity (ClinGen)

periventricular nodular heterotopia · ADStrong

Strong evidence — appropriate for clinical testing

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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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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint

0.13LOEUF

pLI 1.000

Z-score 7.72

OE 0.06 (0.03–0.13)

Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint

2.51Z-score

OE missense 0.80 (0.76–0.85)

1051 obs / 1306.4 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios

LoF OE0.06 (0.03–0.13)

0≤0.351.4

Missense OE0.80 (0.76–0.85)

0≤0.61.4

Synonymous OE1.00

0≤1.21.6

LoF obs/exp: 5 / 79.1Missense obs/exp: 1051 / 1306.4Syn Z: -0.05

0.2598th %ile

GOF

0.3392th %ile

LOF

0.80top 5%

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

LOFprediction above median · LOEUF 0.13

DN1 literature citation

Literature Evidence

DNBecause the gene targeting event in these mice produced a gene encoding a 571-amino acid truncated product of MAP1B, it seems likely that the phenotypes seen arise from the truncated MAP1B product acting in a dominant-negative fashion, rather than a loss of MAP1B function.PMID:9199175

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.