# NM_000092.5(COL4A4):c.1554del (p.Leu519fs)

https://sugi.bio/variant/col4a4-p-leu519fs

## Summary

**COL4A4 p.Leu519fs (c.1554del)** is classified **Likely pathogenic** in COL4A4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-12-29). No gnomAD frequency available for this variant; Associated with autosomal recessive Alport syndrome.

**At a glance:** Likely pathogenic · review: Multiple submitters · rsID rs2059734968 · 2 submitters · 2 linked conditions · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the COL4A4 gene that is considered likely disease-causing, submitted by 2 submitters, and is linked to autosomal recessive Alport 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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant, Autosomal recessive, X-linked dominant |
| Age of onset (of this condition) | Adolescent, Adult, Childhood, Elderly |
| Clinical trials | 2 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | COL4A4 is a diagnostic-grade gene on 5 Genomics England panels |

**Commonly reported features of Alport syndrome** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Hematuria — Very frequent (99-80%)
- Thin glomerular basement membrane — Very frequent (99-80%)
- Diffuse glomerular basement membrane lamellation — Very frequent (99-80%)
- Renal insufficiency — Frequent (79-30%)
- Proteinuria — Frequent (79-30%)
- Hypertension — Frequent (79-30%)
- Mesangial hypercellularity — Frequent (79-30%)
- Renal tubular atrophy — Occasional (29-5%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0000625/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [COL4A4](https://sugi.bio/atlas/gene/COL4A4/) |
| Protein change (HGVS p.) | p.Leu519fs |
| Coding change (HGVS c.) | c.1554del |
| MANE Select transcript | [NM_000092](https://www.ncbi.nlm.nih.gov/nuccore/NM_000092) |
| dbSNP | [rs2059734968](https://www.ncbi.nlm.nih.gov/snp/rs2059734968/) |
| Variant type | Deletion |
| Location | chr2:227088722-227088722 (GRCh38) |
| ClinVar | [VCV1725417](https://www.ncbi.nlm.nih.gov/clinvar/variation/1725417/) |

**All HGVS expressions:** `LRG_231:g.80838del`, `LRG_231t1:c.1551del`, `NC_000002.11:g.227953441del`, `NC_000002.12:g.227088725del`, `NG_011592.1:g.80838del`, `NM_000092.5:c.1554del`

## 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 1.163, GERP -2.57 — weakly conserved position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.607, pLI 3.9265e-10. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 22 of 48**, 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: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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}

**COL4A4** population constraint: LOEUF 0.607, pLI 3.9265e-10, missense-Z 2.2347. *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):

- **Alport syndrome** — Definitive (SD)

## Protein context {#protein}

Residue **519** lies in the 'triple-helical region' region; the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 49.03, 8% of residues very-high.

**2 experimental structure(s)** (PDB): [5NB1](https://www.rcsb.org/structure/5NB1), [6WKU](https://www.rcsb.org/structure/6WKU).

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

*Describes the biological roles of COL4A4 (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:** COL4A4's established molecular role includes extracellular matrix structural constituent. p.Leu519fs falls in the triple-helical region region. In Reactome, COL4A4 is annotated in disease pathway(s) including **Attachment of bacteria to epithelial cells**.

**Disease mechanism (Reactome):** COL4A4 loss or alteration is curated in [Attachment of bacteria to epithelial cells](https://reactome.org/content/detail/R-HSA-9638630).

### Pathways affected {#pathways}

COL4A4 participates in **14 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Attachment of bacteria to epithelial cells](https://reactome.org/content/detail/R-HSA-9638630) | curated |
| [Anchoring fibril formation](https://reactome.org/content/detail/R-HSA-2214320) | curated |
| [Assembly of collagen fibrils and other multimeric structures](https://reactome.org/content/detail/R-HSA-2022090) | curated |
| [Collagen biosynthesis and modifying enzymes](https://reactome.org/content/detail/R-HSA-1650814) | curated |
| [Collagen chain trimerization](https://reactome.org/content/detail/R-HSA-8948216) | curated |
| [Crosslinking of collagen fibrils](https://reactome.org/content/detail/R-HSA-2243919) | curated |
| [Fibronectin matrix formation](https://reactome.org/content/detail/R-HSA-1566977) | curated |
| [NCAM1 interactions](https://reactome.org/content/detail/R-HSA-419037) | curated |
| [Non-integrin membrane-ECM interactions](https://reactome.org/content/detail/R-HSA-3000171) | curated |
| [Signaling by PDGF](https://reactome.org/content/detail/R-HSA-186797) | curated |
| [Collagen degradation](https://reactome.org/content/detail/R-HSA-1442490) | electronic |
| [ECM proteoglycans](https://reactome.org/content/detail/R-HSA-3000178) | electronic |
| [Integrin cell surface interactions](https://reactome.org/content/detail/R-HSA-216083) | electronic |
| [Laminin interactions](https://reactome.org/content/detail/R-HSA-3000157) | electronic |

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

**Molecular function:** extracellular matrix structural constituent, molecular adaptor activity.

**Biological process:** glomerular basement membrane development.

## Clinical significance {#significance}

**Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2023-12-29.

**Submitter consensus:** unanimous (2/2 Likely pathogenic).

**Submission history:** 2 submissions (2022–2023); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Myriad Genetics, Inc. | Likely pathogenic | criteria provided, single submitter | clinical testing | 2022-03-20 |
| Fulgent Genetics, Fulgent Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2023-12-29 |

## Associated conditions {#conditions}

[autosomal recessive Alport syndrome](https://sugi.bio/atlas/disease/autosomal-recessive-alport-syndrome/), [hematuria, benign familial, 1](https://sugi.bio/atlas/disease/hematuria-benign-familial-1/).

**Reported phenotype names (ClinVar):** Autosomal recessive Alport syndrome, Hematuria, benign familial, 1, COL4A3-Related Nephropathy, COL4A4 Alport Syndrome and Thin Basement Membrane Nephropathy, ALPORT SYNDROME 2, AUTOSOMAL RECESSIVE, Alport syndrome type 2, THIN MEMBRANE NEPHROPATHY.

## Similar variants {#similar}

Related COL4A4 variant pages (same residue, condition, or type): [COL4A4 c.1321_1369+3del](/variant/col4a4-c-1321-1369-plus-3del), [COL4A4 c.2385del](/variant/col4a4-c-2385del), [COL4A4 c.327+1_327+5del](/variant/col4a4-c-327-plus-1-327-plus-5del), [COL4A4 c.4091-8_4092del](/variant/col4a4-c-4091-minus-8-4092del), [COL4A4 c.914_930+29del](/variant/col4a4-c-914-930-plus-29del), [COL4A4 p.Ala1573fs](/variant/col4a4-p-ala1573fs), [COL4A4 p.Ala793fs](/variant/col4a4-p-ala793fs), [COL4A4 p.Arg877_Gly888del](/variant/col4a4-p-arg877-gly888del).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); 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 1725417). 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.*