KDF1
protein-codingkeratinocyte differentiation factor 1
Gene summary
Predicted to be involved in several processes, including positive regulation of epidermal cell differentiation; regulation of epidermal cell division; and skin epidermis development. Predicted to act upstream of or within several processes, including keratinocyte development; negative regulation of keratinocyte proliferation; and protein stabilization. Predicted to be located in cytoplasm. Predicted to be active in cell junction. Implicated in ectodermal dysplasia 12. [provided by Alliance of Genome Resources, Jul 2025]
- C1orf172
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~10.9 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0015884
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0015024
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0015024
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0015024
Submitter: ClinGen
KDF1 was first reported in relation to AD KDF1-related tooth agenesis with or without ectodermal dysplasia in 2017 (Shamseldin et al., PMID: 27838789). KDF1-related tooth agenesis with or without ectodermal dysplasia is characterized by tooth agenesis; however some patients may also display variable ectodermal dysplasia. 8 unique missense variants that have been reported in 8 probands in 8 publications (PMIDs: 27838789, 30384154, 30977908, 35641834, 36293320, 37144643, 38501196, 40554824) are included in this curation. The mechanism of pathogenicity is thought to be gain of function. This gene-disease relationship is also supported by animal models, expression studies, protein-protein interactions, functional alteration in patient cells, and biochemical function (PMIDs: 24075906, 30384154, 32239614, 36293320, 36831017). In summary, there is definitive evidence supporting the relationship between KDF1 and AD KDF1-related tooth agenesis with or without ectodermal dysplasia. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Craniofacial Malformations GCEP on the meeting date March 20th, 2025 (SOP Version 11).
Clinical Genomic Database (CGD)
Manifestation: Craniofacial; Dental; Dermatologic
Intervention: General
Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision making, and avoidance of unnecessary testing
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to KDF1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_152365.3. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 1 | 16 | 2 | 19 | ||
| missense | 3 | 3 | 90 | 8 | 4 | 108 |
| nonsense | 0 | |||||
| start loss | 0 | |||||
| frameshift | 0 | |||||
| splice donor/acceptor (+/-2bp) | 0 | |||||
| Total | 3 | 3 | 91 | 24 | 6 | 127 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_689578.2 | 3 | MANE Select | |
| Ensembl | ENSP00000319179.5 | 3 | MANE Select | |
| Ensembl | ENSP00000536958.1 | 3 | Standard | |
| Ensembl | ENSP00000536959.1 | 3 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Biological Process
- keratinocyte development
- regulation of epidermal cell division
- negative regulation of keratinocyte proliferation
- morphogenesis of embryonic epithelium
- positive regulation of epidermal cell differentiation
Cellular Component
- nucleoplasm
- cytoplasm
- cell cortex
- cell junction
- cell leading edge
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000320567
- Coding exons
- 3
- Length
- 10845
- Individuals with no LoFs
- 125735
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 6
- Defined
- 125741
- p
- 0.0000239
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.897 | 225 | 266 | 0.845 | 0.0000174 | 2553 |
| Missense (PolyPhen) | 86 | 121.88 | 0.70563 | 1201 | ||
| Synonymous | 0.125 | 102 | 104 | 0.984 | 0.00000606 | 857 |
| Loss of Function | 2.58 | 4 | 14.6 | 0.273 | 9.62e-7 | 142 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.000065 | 0.000062 | rare |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000045 | 0.000044 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Plays a role in the regulation of the epidermis formation during early development. Required both as an inhibitor of basal cell proliferation and a promoter of differentiation of basal progenitor cell progeny (By similarity). {ECO:0000250|UniProtKB:A2A9F4}.;
- Disease
- DISEASE: Ectodermal dysplasia 12, hypohidrotic/hair/tooth/nail type (ECTD12) [MIM:617337]: A form of ectodermal dysplasia, a disorder due to abnormal development of two or more ectodermal structures. ECTD12 is an autosomal dominant, hypohidrotic form characterized by sparse hair (atrichosis or hypotrichosis), abnormal or missing teeth, and the inability to sweat due to defective development of sweat glands. {ECO:0000269|PubMed:27838789}. Note=The disease may be caused by mutations affecting the gene represented in this entry.;
Intolerance Scores
- RVIS EVS
- -0.07
- RVIS percentile EVS
- 48.78
Essentials
- Essential (gene trap)
- N