MDC1

Chr 6

mediator of DNA damage checkpoint 1

Also known as: NFBD1

NCBI Gene: 9656ENSG00000137337UniProt: Q14676

The protein encoded by this gene contains an N-terminal forkhead domain, two BRCA1 C-terminal (BRCT) motifs and a central domain with 13 repetitions of an approximately 41-amino acid sequence. The encoded protein is required to activate the intra-S phase and G2/M phase cell cycle checkpoints in response to DNA damage. This nuclear protein interacts with phosphorylated histone H2AX near sites of DNA double-strand breaks through its BRCT motifs, and facilitates recruitment of the ATM kinase and meiotic recombination 11 protein complex to DNA damage foci. [provided by RefSeq, Jul 2008]

260
ClinVar variants
8
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— MDC1
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
8 Pathogenic / Likely Pathogenic· 202 VUS of 260 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.
0.54LOEUF
pLI 0.000
Z-score 4.58
OE 0.39 (0.28–0.54)
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.
1.79Z-score
OE missense 0.85 (0.80–0.90)
942 obs / 1109.8 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.0.39 (0.28–0.54)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.85 (0.80–0.90)
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.0.84
0≤1.21.6
LoF obs/exp: 25 / 64.7Missense obs/exp: 942 / 1109.8Syn Z: 2.55

ClinVar Variant Classifications

260 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic7
Likely Pathogenic1
VUS202
Likely Benign35
Benign15
7
Pathogenic
1
Likely Pathogenic
202
VUS
35
Likely Benign
15
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
1
6
0
7
Likely Pathogenic
0
0
1
0
1
VUS
0
201
1
0
202
Likely Benign
0
31
0
4
35
Benign
0
8
1
6
15
Total0241910260

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

View in ClinVar →

Protein Context — Lollipop Plot

MDC1 · protein map & ClinVar variants

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
DNA damage response signaling pathways and targets for radiotherapy sensitization in cancer.
Huang RX et al.·Signal Transduct Target Ther
2020Review
HSF5 Deficiency Causes Male Infertility Involving Spermatogenic Arrest at Meiotic Prophase I in Humans and Mice.
Liu M et al.·Adv Sci (Weinh)
2024
MDC1 maintains active elongation complexes of RNA polymerase II.
Pappas G et al.·Cell Rep
2023
NRDE2 deficiency impairs homologous recombination repair and sensitizes hepatocellular carcinoma to PARP inhibitors.
Wang Y et al.·Cell Genom
2024
LOXL2 reduces susceptibility to PARP inhibitors by promoting super-enhancer-regulated DNA damage repair in high-grade serous ovarian cancer.
Song C et al.·Oncogene
2025
Balancing between cuproplasia and copper-dependent cell death: molecular basis and clinical implications of ATOX1 in cancer.
Suwara J et al.·J Exp Clin Cancer Res
2025Review
Levels of blood CD1c+ mDC1 and CD1chi mDC1 subpopulation reflect disease activity in noninfectious uveitis.
Chen P et al.·Invest Ophthalmol Vis Sci
2014
Novel Variants in MDC1 are Associated With Severe Oligoasthenoteratozoospermia.
Liu X et al.·Clin Genet
2026Case report
Circulating tumor DNA predicts clinical benefits of immune checkpoint blockade in HER2-negative patients with advanced gastric cancer.
He M et al.·Gastric Cancer
2025Cohort
MDC1 is a mediator of the mammalian DNA damage checkpoint.
Stewart GS et al.·Nature
2003
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