NFIB

Chr 9AD

nuclear factor I B

Also known as: CTF, HMGIC/NFIB, MACID, NF-I/B, NF1-B, NFI-B, NFI-RED, NFIB2

NCBI Gene: 4781ENSG00000147862UniProt: O00712

Enables DNA-binding transcription activator activity, RNA polymerase II-specific; RNA polymerase II cis-regulatory region sequence-specific DNA binding activity; and transcription regulator inhibitor activity. Involved in brain development and regulation of DNA-templated transcription. Located in fibrillar center and nucleoplasm. [provided by Alliance of Genome Resources, Jul 2025]

Primary Disease Associations & Inheritance

Macrocephaly, acquired, with impaired intellectual developmentMIM #618286
AD
337
ClinVar variants
164
Pathogenic / LP
1.00
pLI score· haploinsufficient
0
Active trials
Clinical Summary— NFIB
⚡
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.
📋
ClinVar Variants
164 Pathogenic / Likely Pathogenic· 117 VUS of 337 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
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.
0.23LOEUF
pLI 0.999
Z-score 4.55
OE 0.07 (0.03–0.23)
Highly constrained

Highly LoF-intolerant (top ~10% 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.
2.47Z-score
OE missense 0.57 (0.50–0.65)
151 obs / 264.2 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

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.0.07 (0.03–0.23)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.57 (0.50–0.65)
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.1.18
0≤1.21.6
LoF obs/exp: 2 / 27.9Missense obs/exp: 151 / 264.2Syn Z: -1.38

ClinVar Variant Classifications

337 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic134
Likely Pathogenic30
VUS117
Likely Benign24
Benign3
Conflicting2
134
Pathogenic
30
Likely Pathogenic
117
VUS
24
Likely Benign
3
Benign
2
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
6
1
127
0
134
Likely Pathogenic
8
7
15
0
30
VUS
6
92
19
0
117
Likely Benign
0
11
3
10
24
Benign
0
3
0
0
3
Conflicting
—2
Total2011416410310

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

View in ClinVar →

Protein Context — Lollipop Plot

NFIB · protein map & ClinVar variants

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

Gene2Phenotype Curations

NFIB-related macrocephaly, acquired, with impaired intellectual development

strong
ADLoss 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
NUCLEAR FACTOR I/B; NFIB
MIM #600728 · *

Macrocephaly, acquired, with impaired intellectual development

MIM #618286

Molecular basis of disorder known

Autosomal dominant
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Histological types of breast cancer: how special are they?
Weigelt B et al.·Mol Oncol
2010Review
Mechanisms of small cell lung cancer metastasis.
Ko J et al.·EMBO Mol Med
2021Review
m6A Modification Promotes EMT and Metastasis of Castration-Resistant Prostate Cancer by Upregulating NFIB.
Shu F et al.·Cancer Res
2024
HMGA2-WIF1 Rearrangements Characterize a Distinctive Subset of Salivary Pleomorphic Adenomas With Prominent Trabecular (Canalicular Adenoma-like) Morphology.
Agaimy A et al.·Am J Surg Pathol
2022
Molecular pathology of adenoid cystic carcinoma.
Wei S et al.·Histol Histopathol
2025Review
Reversible downregulation of HLA class I in adenoid cystic carcinoma.
Li A et al.·J Immunother Cancer
2025
Nuclear Factor I-B Delays Liver Fibrosis by Inhibiting Chemokine Ligand 5 Transcription.
Chen Q et al.·Adv Sci (Weinh)
2026
NFIB facilitates replication licensing by acting as a genome organizer.
Zhang W et al.·Nat Commun
2023
Solid-Basaloid Adenoid Cystic Carcinoma of the Breast: An Aggressive Subtype Enriched for Notch Pathway and Chromatin Modifier Mutations With MYB Overexpression.
Shamir ER et al.·Mod Pathol
2023
Marked intrafamilial variability of clinical and neuroimaging manifestations in NFIB-related developmental disorder.
Gana S et al.·Am J Med Genet A
2023Case report
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