MAMLD1

Chr XXLR

mastermind like domain containing 1

Also known as: CG1, CXorf6, F18, HYSP2

NCBI Gene: 10046ENSG00000013619UniProt: Q13495

This gene encodes a mastermind-like domain containing protein. This protein may function as a transcriptional co-activator. Mutations in this gene are the cause of X-linked hypospadias type 2. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Apr 2010]

Primary Disease Associations & Inheritance

Hypospadias 2, X-linkedMIM #300758
XLR
289
ClinVar variants
117
Pathogenic / LP
0.63
pLI score
0
Active trials
Clinical Summary— MAMLD1
⚡
Population Constraint (gnomAD)
Moderately constrained gene (pLI 0.63) — some intolerance to loss-of-function variants.
📋
ClinVar Variants
117 Pathogenic / Likely Pathogenic· 103 VUS of 289 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.45LOEUF
pLI 0.626
Z-score 3.39
OE 0.19 (0.10–0.45)
Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
0.60Z-score
OE missense 0.91 (0.83–1.00)
330 obs / 362.1 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.19 (0.10–0.45)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.91 (0.83–1.00)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.09
0≤1.21.6
LoF obs/exp: 4 / 20.6Missense obs/exp: 330 / 362.1Syn Z: -0.90

ClinVar Variant Classifications

289 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic114
Likely Pathogenic3
VUS103
Likely Benign35
Benign27
Conflicting7
114
Pathogenic
3
Likely Pathogenic
103
VUS
35
Likely Benign
27
Benign
7
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
2
0
112
0
114
Likely Pathogenic
0
0
3
0
3
VUS
0
87
14
2
103
Likely Benign
0
14
8
13
35
Benign
0
12
2
13
27
Conflicting
—7
Total211313928289

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

View in ClinVar →

Protein Context — Lollipop Plot

MAMLD1 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

MAMLD1-related hypospadias

strong
Monoallelic X HemizygousLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Hypospadias 2, X-linked

MIM #300758

Molecular basis of disorder known

X-linked recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
MAMLD1 and Differences/Disorders of Sex Development: An Update.
Miyado M et al.·Sex Dev
2022Review
MAMLD1 and 46,XY disorders of sex development.
Ogata T et al.·Semin Reprod Med
2012Review
Clinical and molecular spectrum of 46,XY disorders of sex development that harbour MAMLD1 variations: case series and review of literature.
Li L et al.·Orphanet J Rare Dis
2020Review
A novel MAMLD1 variant in a newborn with hypospadias and elevated 17-hydroxyprogesterone.
Wang J et al.·Hormones (Athens)
2024
[Advance in research on the role of MAMLD1 gene in disorders of sex development].
Gao F et al.·Zhonghua Yi Xue Yi Chuan Xue Za Zhi
2021Review
Clinical applications of and molecular insights from RNA sequencing in a rare disease cohort.
Stark JC et al.·Genome Med
2025Cohort
A New MAMLD1 Variant in an Infant With Microphallus and Hypospadias With Hormonal Pattern Suggesting Partial Hypogonadotropic Hypogonadism-Case Report.
Yeste D et al.·Front Endocrinol (Lausanne)
2022Case report
Novel Splice Site Mutation in MAMLD1 in a Patient with Hypospadias.
Igarashi M et al.·Sex Dev
2015
Pathogenic variations in MAML2 and MAMLD1 contribute to congenital hypothyroidism due to dyshormonogenesis by regulating the Notch signalling pathway.
Wu FY et al.·J Med Genet
2023
Human MAMLD1 Gene Variations Seem Not Sufficient to Explain a 46,XY DSD Phenotype.
Camats N et al.·PLoS One
2015
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools