# NM_182925.5(FLT4):c.89del (p.Pro30fs)

https://sugi.bio/variant/flt4-p-pro30fs

## Summary

**FLT4 p.Pro30fs (c.89del)** is classified **Pathogenic** in FLT4 (ClinVar, Single submitter, 2 submitters; last evaluated 2020-06-10). Very rare (popmax 8.48e-05%, nfe); Associated with congenital heart defects, multiple types, 7.

**At a glance:** Pathogenic · review: Single submitter · rsID rs755445139 · 2 submitters · 1 linked condition · very rare (popmax 8.48e-05%, nfe)

## For patients & families {#patients}

This is a change in the FLT4 gene that is reported as disease-causing, but on limited review, submitted by 2 submitters, and is linked to congenital heart defects, multiple types, 7.

*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:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [FLT4](https://sugi.bio/atlas/gene/FLT4/) |
| Protein change (HGVS p.) | p.Pro30fs |
| Coding change (HGVS c.) | c.89del |
| MANE Select transcript | [NM_182925](https://www.ncbi.nlm.nih.gov/nuccore/NM_182925) |
| dbSNP | [rs755445139](https://www.ncbi.nlm.nih.gov/snp/rs755445139/) |
| Variant type | Deletion |
| Location | chr5:180631748-180631748 (GRCh38) |
| ClinVar | [VCV812612](https://www.ncbi.nlm.nih.gov/clinvar/variation/812612/) |

**All HGVS expressions:** `NC_000005.10:g.180631754del`, `NC_000005.9:g.180058754del`, `NG_011536.1:g.22877del`, `NM_001354989.2:c.89del`, `NM_002020.5:c.89del`, `NM_182925.4:c.89delC`, `NM_182925.5:c.89del`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP -9.067, GERP -2.13 — fast-evolving / accelerated position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. the gene is **loss-of-function-intolerant** (LOEUF 0.265, pLI 1), supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 2 of 30**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **8.48e-05%** (nfe) · 1/1,179,756 in the highest group · 13/1,458,058 alleles overall — very rare (popmax 8.48e-05%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Finnish (not grpmax-eligible) | 0.0198% | 5,044 |
| European (non-Finnish) (grpmax) | 8.48e-05% | 1,179,756 |

Finnish shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

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

**FLT4** population constraint: LOEUF 0.265, pLI 1, missense-Z 3.0272. *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):

- **congenital heart defects, multiple types, 7** — Definitive (AD)
- **lymphatic malformation 1** — Definitive (AD)

## Protein context {#protein}

Residue **30** lies in the ig-like c2-type 1 domain.

AlphaFold model confidence (whole protein): pLDDT 72.82, 28% of residues very-high.

**2 experimental structure(s)** (PDB): [4BSJ](https://www.rcsb.org/structure/4BSJ), [4BSK](https://www.rcsb.org/structure/4BSK).

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

*Describes the biological roles of FLT4 (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:** FLT4's established molecular role includes transmembrane receptor protein tyrosine kinase activity. p.Pro30fs falls in the ig-like c2-type 1 domain.


### Pathways affected {#pathways}

FLT4 participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [VEGF binds to VEGFR leading to receptor dimerization](https://reactome.org/content/detail/R-HSA-195399) | curated |
| [High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells](https://reactome.org/content/detail/R-HSA-9856530) | electronic |
| [NOTCH4 Intracellular Domain Regulates Transcription](https://reactome.org/content/detail/R-HSA-9013695) | electronic |

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

**Molecular function:** transmembrane receptor protein tyrosine kinase activity, vascular endothelial growth factor receptor activity, growth factor binding, protein phosphatase binding, protein homodimerization activity.

**Biological process:** positive regulation of protein phosphorylation, positive regulation of endothelial cell proliferation, lymphangiogenesis, positive regulation of cell population proliferation, positive regulation of vascular endothelial growth factor production, positive regulation of endothelial cell migration.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2020-06-10.

**Submitter consensus:** unanimous (2/2 Pathogenic).

**Submission history:** 2 submissions (2020); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2020-02-18 |
| GeneDx | Pathogenic | criteria provided, single submitter | clinical testing | 2020-06-10 |

## Associated conditions {#conditions}

[congenital heart defects, multiple types, 7](https://sugi.bio/atlas/disease/congenital-heart-defects-multiple-types-7/).

**Reported phenotype names (ClinVar):** Congenital heart defects, multiple types, 7, not provided, none provided.

## Similar variants {#similar}

Related FLT4 variant pages (same residue, condition, or type): [FLT4 p.Glu100fs](/variant/flt4-p-glu100fs), [FLT4 p.Gly975fs](/variant/flt4-p-gly975fs), [FLT4 p.Pro30Leu](/variant/flt4-p-pro30leu), [FLT4 c.3332-356_3894-1373del](/variant/flt4-c-3332-minus-356-3894-minus-1373del), [FLT4 p.Arg318Ter](/variant/flt4-p-arg318ter), [FLT4 p.Pro1137Leu](/variant/flt4-p-pro1137leu), [FLT4 p.Arg1060Gln](/variant/flt4-p-arg1060gln), [FLT4 p.Met1260Leu](/variant/flt4-p-met1260leu).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-06); 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 2026-07-14); 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 812612). 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.*