# NM_000278.5(PAX2):c.501C>T (p.Pro167=)

https://sugi.bio/variant/pax2-p-pro167

## Summary

**PAX2 p.Pro167= (c.501C>T)** is classified **Uncertain significance** in PAX2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-09). Absent from gnomAD v4.1; Associated with renal coloboma syndrome.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs1285286322 · 1 submitter · 2 linked conditions · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the PAX2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, 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.Pro167= |
| Coding change (HGVS c.) | c.501C>T |
| MANE Select transcript | [NM_000278](https://www.ncbi.nlm.nih.gov/nuccore/NM_000278) |
| dbSNP | [rs1285286322](https://www.ncbi.nlm.nih.gov/snp/rs1285286322/) |
| Variant type | single nucleotide variant |
| Location | chr10:100781250-100781250 (GRCh38) |
| ClinVar | [VCV2003818](https://www.ncbi.nlm.nih.gov/clinvar/variation/2003818/) |

**All HGVS expressions:** `NC_000010.10:g.102541007C>T`, `NC_000010.11:g.100781250C>T`, `NG_008680.2:g.50542C>T`, `NM_000278.5:c.501C>T`, `NM_001304569.2:c.594C>T`, `NM_003987.5:c.501C>T`, `NM_003988.5:c.501C>T`, `NM_003989.5:c.501C>T`, `NM_003990.5:c.501C>T`

## 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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **acceptor gain** (Δ 0.26) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 3.254, GERP 2.24, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 17.31**. 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 deltas (raw): acceptor loss **0.01**, donor loss **0.00**, acceptor gain **0.26**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.26**, donor gain **0.00**.
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-06-09.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-06-09 |

## 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, Focal segmental glomerulosclerosis 7, PAPILLORENAL SYNDROME, COLOBOMA OF OPTIC NERVE WITH RENAL DISEASE, 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, CONGENITAL ANOMALIES OF THE KIDNEY AND URINARY TRACT WITH OR WITHOUT OCULAR ABNORMALITIES, CAKUT WITH OR WITHOUT OCULAR ABNORMALITIES.

## Similar variants {#similar}

Related PAX2 variant pages (same residue, condition, or type): [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), [PAX2 p.Gly24Val](/variant/pax2-p-gly24val).

### 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 2003818). 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.*