# NM_000092.5(COL4A4):c.297T>A (p.Pro99=)

https://sugi.bio/variant/col4a4-p-pro99

## Summary

**COL4A4 p.Pro99= (c.297T>A)** is classified **Likely benign** in COL4A4 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2023-11-22). Very rare (popmax 0.00167%, amr); Associated with hematuria, benign familial.

**At a glance:** Likely benign · review: Multiple submitters · rsID rs1576662029 · 3 submitters · 2 linked conditions · very rare (popmax 0.00167%, amr)

## For patients & families {#patients}

This is a change in the COL4A4 gene that is classified as likely benign — not considered disease-causing, submitted by 3 submitters, and is linked to hematuria, benign familial.

*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.*

|  |  |
| --- | --- |
| Diagnostic panels | COL4A4 is a diagnostic-grade gene on 5 Genomics England panels |

**Support & next steps:** [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.Pro99= |
| Coding change (HGVS c.) | c.297T>A |
| MANE Select transcript | [NM_000092](https://www.ncbi.nlm.nih.gov/nuccore/NM_000092) |
| dbSNP | [rs1576662029](https://www.ncbi.nlm.nih.gov/snp/rs1576662029/) |
| Variant type | single nucleotide variant |
| Location | chr2:227121044-227121044 (GRCh38) |
| ClinVar | [VCV666680](https://www.ncbi.nlm.nih.gov/clinvar/variation/666680/) |

**All HGVS expressions:** `LRG_231:g.48516T>A`, `LRG_231t1:c.297T>A`, `NC_000002.11:g.227985760A>T`, `NC_000002.12:g.227121044A>T`, `NG_011592.1:g.48516T>A`, `NM_000092.5:c.297T>A`

## 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 0.618, GERP -1.24, phastCons 0.003 — weakly conserved position
- CADD: **PHRED 7.341**. 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.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.00167%** (amr) · 1/60,020 in the highest group · 1/1,461,878 alleles overall — very rare (popmax 0.00167%, amr).

*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 **99** lies in the 'disordered' region; the 'triple-helical region' 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.Pro99= falls in the disordered 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 benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2023-11-22.

**Submitter consensus:** unanimous (3/3 Likely benign).

**Submission history:** 3 submissions (2018–2023); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Likely benign | criteria provided, single submitter | clinical testing | 2018-02-10 |
| Fulgent Genetics, Fulgent Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2021-11-29 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2023-11-22 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Benign familial hematuria, not specified, not provided, Autosomal recessive Alport syndrome, COL4A3-Related Nephropathy, COL4A4 Alport Syndrome and Thin Basement Membrane Nephropathy, Alport syndrome type 2, ALPORT SYNDROME 2, AUTOSOMAL RECESSIVE, AllHighlyPenetrant, none provided.

## Same-residue context {#hotspot}

Residue **99** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [COL4A4 p.Pro99fs](/variant/col4a4-p-pro99fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related COL4A4 variant pages (same residue, condition, or type): [COL4A4 p.Pro99fs](/variant/col4a4-p-pro99fs), [COL4A4 c.1030-2A>C](/variant/col4a4-c-1030-minus-2a-c), [COL4A4 c.1099+1G>T](/variant/col4a4-c-1099-plus-1g-t), [COL4A4 c.1369+1G>A](/variant/col4a4-c-1369-plus-1g-a), [COL4A4 c.1459+1G>A](/variant/col4a4-c-1459-plus-1g-a), [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).

### 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 666680). 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.*