NFIA

Chr 1AD

nuclear factor I A

Also known as: BRMUTD, C1DELp32p31, CTF, DEL1P32P31, NF-I/A, NF1-A, NFI-A, NFI-L

NCBI Gene: 4774ENSG00000162599UniProt: Q12857

This gene encodes a member of the NF1 (nuclear factor 1) family of transcription factors. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2011]

Primary Disease Associations & Inheritance

Brain malformations with or without urinary tract defectsMIM #613735
AD
454
ClinVar variants
90
Pathogenic / LP
1.00
pLI score· haploinsufficient
1
Active trials
Clinical Summary— NFIA
🧬
Gene-Disease Validity (ClinGen)
brain malformations with or without urinary tract defects · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
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
90 Pathogenic / Likely Pathogenic· 171 VUS of 454 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Dual constrained — LoF & missense intolerant
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.
0.20LOEUF
pLI 1.000
Z-score 4.85
OE 0.06 (0.03–0.20)
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.
3.23Z-score
OE missense 0.49 (0.43–0.56)
158 obs / 320.9 exp
Constrained

Highly missense-constrained (top ~0.1%)

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.0.06 (0.03–0.20)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.49 (0.43–0.56)
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.1.01
0≤1.21.6
LoF obs/exp: 2 / 31.2Missense obs/exp: 158 / 320.9Syn Z: -0.11

ClinVar Variant Classifications

454 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic53
Likely Pathogenic37
VUS171
Likely Benign142
Benign42
Conflicting9
53
Pathogenic
37
Likely Pathogenic
171
VUS
142
Likely Benign
42
Benign
9
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
16
3
34
0
53
Likely Pathogenic
19
7
11
0
37
VUS
2
132
37
0
171
Likely Benign
0
8
65
69
142
Benign
0
0
41
1
42
Conflicting
—9
Total3715018870454

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

View in ClinVar →

Protein Context — Lollipop Plot

NFIA · protein map & ClinVar variants

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

Gene2Phenotype Curations

NFIA-related macrocephaly with intellectual disability

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/A; NFIA
MIM #600727 · *

Brain malformations with or without urinary tract defects

MIM #613735

Molecular basis of disorder known

Autosomal dominant
📖
GeneReview available — NFIA
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Phenotypic Spectrum of NFIA Haploinsufficiency: Two Additional Cases and Review of the Literature.
Bertini V et al.·Genes (Basel)
2022Review
Functional profiling of murine glioma models highlights targetable immune evasion phenotypes.
Mikolajewicz N et al.·Acta Neuropathol
2024Functional
Identification and characterization of the long non-coding RNA NFIA-AS2 as a novel locus for body mass index in American Indians.
Bandesh K et al.·Int J Obes (Lond)
2023Meta-analysis
Prenatal Diagnosed Agenesis of the Corpus Callosum: Identifying the Underlying Genetic Etiologies.
Wei X et al.·Prenat Diagn
2024
Clinical-Genetic Approach to Conditions with Macrocephaly and ASD/Behaviour Abnormalities: Variants in PTEN and PPP2R5D Are the Most Recurrent Gene Mutations in a Patient-Oriented Diagnostic Strategy.
L'Erario FF et al.·Genes (Basel)
2025
The p.Thr395Met missense variant of NFIA found in a patient with intellectual disability is a defective variant.
Ogura Y et al.·Am J Med Genet A
2022Case report
Ligand-specific regulation of a binary enhancer code dictating cellular senescence.
Suter T et al.·Proc Natl Acad Sci U S A
2025
Pathogenic variant in NFIA associated with subdural hematomas mimicking nonaccidental trauma.
Wongkittichote P et al.·Am J Med Genet A
2022Case report
The nuclear factor I/A (NFIA) gene is associated with the asthma plus rhinitis phenotype.
Dizier MH et al.·J Allergy Clin Immunol
2014Meta-analysis
Optical genome mapping unveils hidden structural variants in neurodevelopmental disorders.
Schrauwen I et al.·Sci Rep
2024
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Downregulation of NFIA facilitates glycolysis, histone lactylation, and activation of the FN1-integrin α5β1 pathway in pancreatic cancer.
Zhang X et al.·Apoptosis
2026
Biochemical and structural studies of NFIA and NFIC reveal a conserved mechanism for specific DNA recognition and provide insight into potential pathogenicity of disease-associated mutations.
Pan S et al.·Acta Biochim Biophys Sin (Shanghai)
2025Functional
Transcriptional control of brown adipocyte differentiation and function by NFIA: recent perspectives on deciphering metabolic diseases.
Hiraike Y.·J Biochem
2025🔓 Open Access
NFIA-dependent upregulation of SMC4 promotes metastasis and metabolic reprogramming in glioma.
Li G et al.·Front Oncol
2025🔓 Open Access
NFIA regulates articular chondrocyte fatty acid metabolism and joint homeostasis.
Wang C et al.·Sci Transl Med
2025
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Neurofibromatosis Type 1

Prevalence, Clinical Characteristics, Progression, and Management of Neurofibromatosis Type 1 in Egypt (NF1-Egy)

RECRUITING
NCT07221331AstraZenecaStarted 2025-11-19

External Resources

Links to major genomics databases and tools