# NM_005251.2(FOXC2):c.(?_1)_(1506_?)del

https://sugi.bio/variant/foxc2-c-1

## Summary

**FOXC2 c.(?_1** is classified **Likely pathogenic** in FOXC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-04-16). Associated with lymphedema-distichiasis syndrome.

**At a glance:** Likely pathogenic · review: Single submitter · 1 submitter · 1 linked condition

## For patients & families {#patients}

This is a change in the FOXC2 gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to lymphedema-distichiasis syndrome.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0000333/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [FOXC2](https://sugi.bio/atlas/gene/FOXC2/) |
| Coding change (HGVS c.) | c.(?_1 |
| MANE Select transcript | [NM_005251](https://www.ncbi.nlm.nih.gov/nuccore/NM_005251) |
| Variant type | Deletion |
| Location | chr16:None-None (GRCh38) |
| ClinVar | [VCV623171](https://www.ncbi.nlm.nih.gov/clinvar/variation/623171/) |

**All HGVS expressions:** `NC_000016.10:g.(?_86567336)_(86568841_?)del`, `NC_000016.9:g.(?_86600942)_(86602447_?)del`

## Gene constraint & dosage {#gene-context}

**FOXC2** population constraint: LOEUF 1.807, pLI 0.00066521, missense-Z -3.0645; ClinGen dosage — haploinsufficiency 3/3, triplosensitivity 0/3. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **lymphedema-distichiasis syndrome** — Definitive (AD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 56.45, 16% of residues very-high.

**8 experimental structure(s)** (PDB): [1D5V](https://www.rcsb.org/structure/1D5V), [6AKO](https://www.rcsb.org/structure/6AKO), [6AKP](https://www.rcsb.org/structure/6AKP), [6LBM](https://www.rcsb.org/structure/6LBM), [6O3T](https://www.rcsb.org/structure/6O3T), [9VRQ](https://www.rcsb.org/structure/9VRQ).

## What this gene does {#gene-function}

*Describes the biological roles of FOXC2 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** FOXC2's established molecular role includes RNA polymerase II transcription regulatory region sequence-specific DNA binding.


### Pathways affected {#pathways}

FOXC2 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Formation of intermediate mesoderm](https://reactome.org/content/detail/R-HSA-9761174) | electronic |
| [Formation of the ureteric bud](https://reactome.org/content/detail/R-HSA-9830674) | electronic |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** RNA polymerase II transcription regulatory region sequence-specific DNA binding, RNA polymerase II cis-regulatory region sequence-specific DNA binding, DNA-binding transcription activator activity, DNA-binding transcription activator activity, RNA polymerase II-specific, chromatin DNA binding, identical protein binding.

**Biological process:** lymphangiogenesis, heart development, insulin receptor signaling pathway, response to hormone, positive regulation of DNA-templated transcription, positive regulation of transcription by RNA polymerase II.

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2018-04-16.

**Submitter consensus:** unanimous (1/1 Likely pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota | Likely pathogenic | criteria provided, single submitter | clinical testing | 2018-04-16 |

## Associated conditions {#conditions}

[lymphedema-distichiasis syndrome](https://sugi.bio/atlas/disease/lymphedema-distichiasis-syndrome/).

**Reported phenotype names (ClinVar):** Distichiasis-lymphedema syndrome, LYMPHEDEMA WITH DISTICHIASIS.

## Similar variants {#similar}

Related FOXC2 variant pages (same residue, condition, or type): [FOXC2 p.Tyr305fs](/variant/foxc2-p-tyr305fs), [FOXC2 p.Gln390_His396del](/variant/foxc2-p-gln390-his396del), [FOXC2 p.Ala325fs](/variant/foxc2-p-ala325fs), [FOXC2 p.Gln407fs](/variant/foxc2-p-gln407fs), [FOXC2 p.Pro403fs](/variant/foxc2-p-pro403fs), [FOXC2 p.Lys177del](/variant/foxc2-p-lys177del), [FOXC2 p.Gln444fs](/variant/foxc2-p-gln444fs), [FOXC2 p.Gly97fs](/variant/foxc2-p-gly97fs).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 623171). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*