# NM_000278.5(PAX2):c.909A>C (p.Pro303=)

https://sugi.bio/variant/pax2-p-pro303

## Summary

**PAX2 p.Pro303= (c.909A>C)** is classified **Benign** in PAX2 (ClinVar, Multiple submitters, 12 submitters; last evaluated 2026-02-04). Common (popmax 75.1%, afr) — too common for a highly-penetrant pathogenic allele; Associated with renal coloboma syndrome.

**At a glance:** Benign · review: Multiple submitters · rsID rs1800898 · 12 submitters · 2 linked conditions · common (popmax 75.1%, afr) — too common for a highly-penetrant pathogenic allele

## For patients & families {#patients}

This is a change in the PAX2 gene that is classified as benign — not considered disease-causing, submitted by 12 submitters, and is linked to renal coloboma 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.*

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0004106/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [PAX2](https://sugi.bio/atlas/gene/PAX2/) |
| Protein change (HGVS p.) | p.Pro303= |
| Coding change (HGVS c.) | c.909A>C |
| MANE Select transcript | [NM_000278](https://www.ncbi.nlm.nih.gov/nuccore/NM_000278) |
| dbSNP | [rs1800898](https://www.ncbi.nlm.nih.gov/snp/rs1800898/) |
| Variant type | single nucleotide variant |
| Location | chr10:100809226-100809226 (GRCh38) |
| ClinVar | [VCV156300](https://www.ncbi.nlm.nih.gov/clinvar/variation/156300/) |

**All HGVS expressions:** `NC_000010.10:g.102568983A>C`, `NC_000010.11:g.100809226A>C`, `NG_008680.2:g.78518A>C`, `NM_000278.5:c.909A>C`, `NM_001304569.2:c.1002A>C`, `NM_003987.5:c.978A>C`, `NM_003988.5:c.909A>C`, `NM_003989.5:c.909A>C`, `NM_003990.5:c.978A>C`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — common (popmax 75.1%, afr) — too common for a highly-penetrant pathogenic allele.

- **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 -5.21, GERP -3.55 — fast-evolving / accelerated position
- CADD: **PHRED 0.634**. 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 **75.1%** (afr) · FAF95 74.6% · FAF99 74.4% · 56,276/74,934 in the highest group · 479,157/1,612,774 alleles overall — common (popmax 75.1%, afr) — too common for a highly-penetrant pathogenic allele.

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 75.1% | 1 |
| Middle Eastern | 41% | 2 |
| South Asian | 32.3% | 3 |
| Amish (not grpmax-eligible) | 32.1% | 3 |
| Remaining individuals (not grpmax-eligible) | 30.9% | 3 |
| European (non-Finnish) | 28.4% | 4 |
| Ashkenazi Jewish (not grpmax-eligible) | 25.2% | 4 |
| Admixed American | 21.9% | 5 |
| Finnish (not grpmax-eligible) | 18.3% | 5 |
| East Asian | 9.97% | 10 |

*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}

**PAX2** population constraint: LOEUF 0.451, pLI 0.99743, missense-Z 1.8762; 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):

- **focal segmental glomerulosclerosis 7** — Definitive (AD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 61.52, 27% of residues very-high.

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

*Describes the biological roles of PAX2 (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:** PAX2's established molecular role includes transcription cis-regulatory region binding.


### Pathways affected {#pathways}

PAX2 participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Formation of intermediate mesoderm](https://reactome.org/content/detail/R-HSA-9761174) | electronic |
| [Formation of the nephric duct](https://reactome.org/content/detail/R-HSA-9830364) | electronic |
| [Formation of the ureteric bud](https://reactome.org/content/detail/R-HSA-9830674) | electronic |

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

**Molecular function:** transcription cis-regulatory region binding, cis-regulatory region sequence-specific DNA binding, DNA binding, DNA-binding transcription factor activity, transcription factor binding, sequence-specific double-stranded DNA binding.

**Biological process:** branching involved in ureteric bud morphogenesis, regulation of metanephros size, negative regulation of apoptotic process, negative regulation of DNA-templated transcription, positive regulation of DNA-templated transcription, positive regulation of transcription by RNA polymerase II.

## Clinical significance {#significance}

**Benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-02-04.

**Submitter consensus:** conflicting (12 Benign, 1 not provided).

**Submission history:** 13 submissions (2015–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | Benign | no assertion criteria provided | clinical testing |  |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |
| Blueprint Genetics | Benign | criteria provided, single submitter | clinical testing | 2024-11-27 |
| PreventionGenetics, part of Exact Sciences | Benign | criteria provided, single submitter | clinical testing |  |
| Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | Benign | no assertion criteria provided | clinical testing |  |
| Genome Diagnostics Laboratory, University Medical Center Utrecht | Benign | no assertion criteria provided | clinical testing |  |
| Genome-Nilou Lab | Benign | criteria provided, single submitter | clinical testing | 2021-09-05 |
| Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan | Benign | criteria provided, single submitter | clinical testing | 2024-07-15 |
| Mayo Clinic Laboratories, Mayo Clinic | Benign | criteria provided, single submitter | clinical testing | 2022-03-09 |
| ClinVar Staff, National Center for Biotechnology Information (NCBI) | not provided | no classification provided | not provided |  |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2015-03-03 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-02-04 |

## Associated conditions {#conditions}

[renal coloboma syndrome](https://sugi.bio/atlas/disease/renal-coloboma-syndrome/), [focal segmental glomerulosclerosis 7](https://sugi.bio/atlas/disease/focal-segmental-glomerulosclerosis-7/).

**Reported phenotype names (ClinVar):** Renal coloboma syndrome, not provided, not specified, Focal segmental glomerulosclerosis 7, CONGENITAL ANOMALIES OF THE KIDNEY AND URINARY TRACT WITH OR WITHOUT OCULAR ABNORMALITIES, CAKUT WITH OR WITHOUT OCULAR ABNORMALITIES, OPTIC COLOBOMA, VESICOURETERAL REFLUX, AND RENAL ANOMALIES, OPTIC NERVE COLOBOMA WITH RENAL DISEASE, RENAL-COLOBOMA SYNDROME WITH MACULAR ABNORMALITIES, PAPILLORENAL SYNDROME WITH MILD OCULAR ABNORMALITIES.

## Similar variants {#similar}

Related PAX2 variant pages (same residue, condition, or type): [PAX2 p.Pro303Ala](/variant/pax2-p-pro303ala), [PAX2 c.212+1G>T](/variant/pax2-c-212-plus-1g-t), [PAX2 c.213-8C>A](/variant/pax2-c-213-minus-8c-a), [PAX2 c.792+2T>C](/variant/pax2-c-792-plus-2t-c), [PAX2 p.Arg104Ter](/variant/pax2-p-arg104ter), [PAX2 p.Arg115Ter](/variant/pax2-p-arg115ter), [PAX2 p.Arg140Trp](/variant/pax2-p-arg140trp), [PAX2 p.Arg229Ter](/variant/pax2-p-arg229ter).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 156300). 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.*