# NM_012203.2(GRHPR):c.8C>T (p.Pro3Leu)

https://sugi.bio/variant/grhpr-p-pro3leu

## Summary

**GRHPR p.Pro3Leu (c.8C>T)** is classified **Uncertain significance** in GRHPR (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-26). AlphaMissense: likely benign (0.1789); Very rare (popmax 0.00269%, afr); Associated with Nephrolithiasis/nephrocalcinosis.

**At a glance:** Uncertain significance · review: Multiple submitters · 2 submitters · 2 linked conditions · AlphaMissense likely benign · very rare (popmax 0.00269%, afr)

## For patients & families {#patients}

This is a change in the GRHPR gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 submitters, and is linked to Nephrolithiasis/nephrocalcinosis.

*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 | [GRHPR](https://sugi.bio/atlas/gene/GRHPR/) |
| Protein change (HGVS p.) | p.Pro3Leu |
| Coding change (HGVS c.) | c.8C>T |
| MANE Select transcript | [NM_012203](https://www.ncbi.nlm.nih.gov/nuccore/NM_012203) |
| Variant type | single nucleotide variant |
| Location | chr9:37422758-37422758 (GRCh38) |
| ClinVar | [VCV3597316](https://www.ncbi.nlm.nih.gov/clinvar/variation/3597316/) |

**All HGVS expressions:** `NC_000009.11:g.37422755C>T`, `NC_000009.12:g.37422758C>T`, `NG_008135.1:g.5049C>T`, `NG_116256.1:g.817C>T`, `NG_116257.1:g.191C>T`, `NM_012203.1:c.8C>T`, `NM_012203.2:c.8C>T`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.1789)
- REVEL 0.209 (benign-leaning) — agrees with AlphaMissense
- SaProt LLR -5.478 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP -3.541, GERP -4.19 — fast-evolving / accelerated position
- CADD: **PHRED 3.426**. 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 0.87** across the covering region of the MANE Select transcript (37,422,751–37,436,779), spanning 14,028 bp. Chi-square p 0.0084. 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 (C>A, Δ0.64 donor 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 **0.00269%** (afr) · FAF95 0.000447% · FAF99 0.000167% · 2/74,278 in the highest group · 2/1,434,644 alleles overall — very rare (popmax 0.00269%, afr).

*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}

**GRHPR** population constraint: LOEUF 1.313, pLI 3.7191e-09, missense-Z 0.86189; ClinGen dosage — haploinsufficiency 30, triplosensitivity 0 (0–3 scale). *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 96.80, 98% of residues very-high.

**4 experimental structure(s)** (PDB): [2GCG](https://www.rcsb.org/structure/2GCG), [2H1S](https://www.rcsb.org/structure/2H1S), [2Q50](https://www.rcsb.org/structure/2Q50), [2WWR](https://www.rcsb.org/structure/2WWR).

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

*Describes the biological roles of GRHPR (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:** GRHPR's established molecular role includes hydroxypyruvate reductase (NADH) activity.


### Pathways affected {#pathways}

GRHPR participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Glyoxylate metabolism and glycine degradation](https://reactome.org/content/detail/R-HSA-389661) | curated |

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

**Molecular function:** hydroxypyruvate reductase (NADH) activity, hydroxypyruvate reductase [NAD(P)H] activity, glyoxylate reductase (NADPH) activity, protein homodimerization activity, NADPH binding.

**Biological process:** glyoxylate metabolic process.

## Clinical significance {#significance}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-08-26.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2024–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Fulgent Genetics, Fulgent Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-03-18 |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-08-26 |

## Associated conditions {#conditions}

[Nephrolithiasis/nephrocalcinosis](https://sugi.bio/atlas/disease/nephrolithiasis-nephrocalcinosis/), [primary hyperoxaluria type 2](https://sugi.bio/atlas/disease/primary-hyperoxaluria-type-2/).

**Reported phenotype names (ClinVar):** Nephrolithiasis/nephrocalcinosis, Primary hyperoxaluria, type II, OXALOSIS II, Primary hyperoxaluria type 2, D-GLYCERATE DEHYDROGENASE DEFICIENCY, GLYCERIC ACIDURIA, GLYOXYLATE REDUCTASE/HYDROXYPYRUVATE REDUCTASE DEFICIENCY.

## Similar variants {#similar}

Related GRHPR variant pages (same residue, condition, or type): [GRHPR p.Pro3=](/variant/grhpr-p-pro3), [GRHPR c.404+5G>A](/variant/grhpr-c-404-plus-5g-a), [GRHPR c.493+2T>A](/variant/grhpr-c-493-plus-2t-a), [GRHPR c.494-2A>G](/variant/grhpr-c-494-minus-2a-g), [GRHPR c.734+1G>A](/variant/grhpr-c-734-plus-1g-a), [GRHPR c.735-1G>A](/variant/grhpr-c-735-minus-1g-a), [GRHPR c.83+1G>C](/variant/grhpr-c-83-plus-1g-c), [GRHPR c.84-2A>G](/variant/grhpr-c-84-minus-2a-g).

### 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 3597316). 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.*