# NM_033380.3(COL4A5):c.2294del (p.Pro765fs)

https://sugi.bio/variant/col4a5-p-pro765fs

## Summary

**COL4A5 p.Pro765fs (c.2294del)** is classified **Pathogenic/Likely pathogenic** in COL4A5 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-06-09). No gnomAD frequency available for this variant.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs2066735315 · 2 submitters · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the COL4A5 gene that is considered likely disease-causing, submitted by 2 submitters.

*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 | [COL4A5](https://sugi.bio/atlas/gene/COL4A5/) |
| Protein change (HGVS p.) | p.Pro765fs |
| Coding change (HGVS c.) | c.2294del |
| MANE Select transcript | [NM_033380](https://www.ncbi.nlm.nih.gov/nuccore/NM_033380) |
| dbSNP | [rs2066735315](https://www.ncbi.nlm.nih.gov/snp/rs2066735315/) |
| Variant type | Deletion |
| Location | chrX:108606790-108606790 (GRCh38) |
| ClinVar | [VCV977198](https://www.ncbi.nlm.nih.gov/clinvar/variation/977198/) |

**All HGVS expressions:** `LRG_232:g.171868del`, `LRG_232t1:c.2294del`, `LRG_232t2:c.2294del`, `NC_000023.10:g.107850021del`, `NC_000023.11:g.108606791del`, `NG_011977.2:g.171868del`, `NM_000495.5:c.2294del`, `NM_033380.3:c.2294del`

## 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 0.019, GERP -1.8, phastCons 0.812 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. ClinGen curates **sufficient evidence for haploinsufficiency** in this gene, supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 29 of 53**, 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}

**COL4A5** population constraint: 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):

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

## Protein context {#protein}

Residue **765** lies in the 'triple-helical region' region; the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 49.04, 15% of residues very-high.

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

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

*Describes the biological roles of COL4A5 (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:** COL4A5's established molecular role includes extracellular matrix structural constituent conferring tensile strength. p.Pro765fs falls in the triple-helical region region. In Reactome, COL4A5 is annotated in disease pathway(s) including **Attachment of bacteria to epithelial cells**.

**Disease mechanism (Reactome):** COL4A5 loss or alteration is curated in [Attachment of bacteria to epithelial cells](https://reactome.org/content/detail/R-HSA-9638630).

### Pathways affected {#pathways}

COL4A5 participates in **15 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 |
| [Regulation of expression of SLITs and ROBOs](https://reactome.org/content/detail/R-HSA-9010553) | electronic |

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

**Molecular function:** extracellular matrix structural constituent conferring tensile strength.

## Clinical significance {#significance}

**Pathogenic/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2023-06-09.

**Submitter consensus:** conflicting (1 Likely pathogenic, 1 Pathogenic).

**Submission history:** 2 submissions (2020–2023); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Likely pathogenic | criteria provided, single submitter | clinical testing | 2020-07-06 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2023-06-09 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related COL4A5 variant pages (same residue, condition, or type): [COL4A5 p.Pro765=](/variant/col4a5-p-pro765), [COL4A5 c.275_276+2del](/variant/col4a5-c-275-276-plus-2del), [COL4A5 p.Asn607fs](/variant/col4a5-p-asn607fs), [COL4A5 p.Asp1540fs](/variant/col4a5-p-asp1540fs), [COL4A5 p.Asp989_Gly994del](/variant/col4a5-p-asp989-gly994del), [COL4A5 p.Glu1355fs](/variant/col4a5-p-glu1355fs), [COL4A5 p.Gly1369fs](/variant/col4a5-p-gly1369fs), [COL4A5 p.Gly204fs](/variant/col4a5-p-gly204fs).

### 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 2026-10-14); 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 977198). 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.*