# NM_000092.5(COL4A4):c.2399C>G (p.Pro800Arg)

https://sugi.bio/variant/col4a4-p-pro800arg

## Summary

**COL4A4 p.Pro800Arg (c.2399C>G)** is classified **Conflicting classifications of pathogenicity** in COL4A4 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-01-09). AlphaMissense: likely benign (0.0869); Very rare (popmax 0.000847%, nfe); Associated with Alport syndrome.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs200714000 · 3 submitters · 1 linked condition · AlphaMissense likely benign · very rare (popmax 0.000847%, nfe)

## For patients & families {#patients}

This is a change in the COL4A4 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 3 submitters, and is linked to 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 | 30 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/0005785/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.Pro800Arg |
| Coding change (HGVS c.) | c.2399C>G |
| MANE Select transcript | [NM_000092](https://www.ncbi.nlm.nih.gov/nuccore/NM_000092) |
| dbSNP | [rs200714000](https://www.ncbi.nlm.nih.gov/snp/rs200714000/) |
| Variant type | single nucleotide variant |
| Location | chr2:227057585-227057585 (GRCh38) |
| ClinVar | [VCV334719](https://www.ncbi.nlm.nih.gov/clinvar/variation/334719/) |

**All HGVS expressions:** `LRG_231:g.111975C>G`, `LRG_231t1:c.2399C>G`, `NC_000002.11:g.227922301G>C`, `NC_000002.12:g.227057585G>C`, `NG_011592.1:g.111975C>G`, `NM_000092.5:c.2399C>G`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.0869)
- REVEL 0.647 (pathogenic-leaning) — differs from AlphaMissense
- SaProt LLR -9.381 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** REVEL calls this damaging; AlphaMissense and SaProt do not
- Conservation: phyloP 6.576, GERP 1.84, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 24.8**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- Regional missense constraint: **o/e 0.91** across the covering region of the MANE Select transcript (227,007,328–227,147,483), spanning 140,155 bp. Chi-square p 1.4e-05. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (G>A, Δ0.37 acceptor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.000847%** (nfe) · FAF95 0.000429% · FAF99 0.000312% · 10/1,180,030 in the highest group · 440/1,614,154 alleles overall — very rare (popmax 0.000847%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Finnish (not grpmax-eligible) | 0.667% | 150 |
| Remaining individuals (not grpmax-eligible) | 0.0048% | 20,837 |
| European (non-Finnish) (grpmax) | 0.000847% | 118,003 |

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}

**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 **800** 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.Pro800Arg 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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2026-01-09.

**Submitter consensus:** conflicting (1 Uncertain significance, 1 Benign, 1 Likely benign).

**Submission history:** 3 submissions (2018–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Illumina Laboratory Services, Illumina | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-01-12 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-01-09 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-21 |

## Associated conditions {#conditions}

[Alport syndrome](https://sugi.bio/atlas/disease/alport-syndrome/).

**Reported phenotype names (ClinVar):** Alport syndrome, not provided, not specified, none provided, Hemorrhagic familial nephritis, Hemorrhagic hereditary nephritis, Congenital hereditary hematuria, AllHighlyPenetrant.

## Same-residue context {#hotspot}

Residue **800** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [COL4A4 p.Pro800fs](/variant/col4a4-p-pro800fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related COL4A4 variant pages (same residue, condition, or type): [COL4A4 p.Pro800=](/variant/col4a4-p-pro800), [COL4A4 c.1030-2A>C](/variant/col4a4-c-1030-minus-2a-c), [COL4A4 c.1369+1G>A](/variant/col4a4-c-1369-plus-1g-a), [COL4A4 c.1370-2A>C](/variant/col4a4-c-1370-minus-2a-c), [COL4A4 c.1696+1G>A](/variant/col4a4-c-1696-plus-1g-a), [COL4A4 c.1696+1G>T](/variant/col4a4-c-1696-plus-1g-t), [COL4A4 c.1697-1G>A](/variant/col4a4-c-1697-minus-1g-a), [COL4A4 c.1803+2T>C](/variant/col4a4-c-1803-plus-2t-c).

### 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 334719). 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.*