MAD1L1

Chr 7AR

mitotic arrest deficient 1 like 1

Also known as: MAD1, MVA7, PIG9, TP53I9, TXBP181

NCBI Gene: 8379 ENSG00000002822 UniProt: Q9Y6D9 OMIM: 602686

MAD1L1 encodes a component of the mitotic spindle-assembly checkpoint that prevents anaphase until all chromosomes are properly aligned at the metaphase plate, forming complexes with MAD2L1 at kinetochores to ensure proper mitotic signaling. Autosomal recessive mutations cause mosaic variegated aneuploidy syndrome 7 with inflammation and tumor predisposition. The gene is extremely intolerant to loss-of-function variants (pLI near 1.0), indicating that complete loss of function is likely embryonic lethal.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

MAD1L1 is a component of the mitotic spindle-assembly checkpoint that prevents the onset of anaphase until all chromosome are properly aligned at the metaphase plate. MAD1L1 functions as a homodimer and interacts with MAD2L1. MAD1L1 may play a role in cell cycle control and tumor suppression. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2015]

OMIM ResearchGenerating clinical summary…

DNmechanismARLOEUF 0.973 OMIM phenotypes

Clinical Summary— MAD1L1

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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

7 unique Pathogenic / Likely Pathogenic· 121 VUS of 178 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?

0.97LOEUF

pLI 0.000

Z-score 1.71

OE 0.71 (0.53–0.97)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.03Z-score

OE missense 1.00 (0.92–1.08)

460 obs / 461.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.71 (0.53–0.97)

0≤0.351.4

Missense OE?1.00 (0.92–1.08)

0≤0.61.4

Synonymous OE?1.07

0≤1.21.6

LoF obs/exp: 30 / 42.0Missense obs/exp: 460 / 461.5Syn Z: -0.81

This gene — mechanism propensity

0.6839th %ile

GOF

0.4875th %ile

LOF

0.3647th %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

178 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic5

Likely Pathogenic2

VUS121

Likely Benign13

Benign4

Pathogenic

Likely Pathogenic

121

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	5	0	0	0	5
Likely Pathogenic	2	0	0	0	2
VUS	0	121	0	0	121
Likely Benign	1	4	2	6	13
Benign	0	0	1	3	4
Total	8	125	3	9	145

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

View in ClinVar →

40 pathogenic / likely-pathogenic (of 70) ClinVar copy-number / structural variants overlap MAD1L1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →