# NM_012203.2(GRHPR):c.608_609del (p.Pro203fs)

https://sugi.bio/variant/grhpr-p-pro203fs

## Summary

**GRHPR p.Pro203fs (c.608_609del)** is classified **Pathogenic/Likely pathogenic** in GRHPR (ClinVar, Multiple submitters, 8 submitters; last evaluated 2025-01-27). Very rare (popmax 0.00223%, eas); Associated with primary hyperoxaluria type 2.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs180177316 · 8 submitters · 1 linked condition · very rare (popmax 0.00223%, eas)

## For patients & families {#patients}

This is a change in the GRHPR gene that is considered likely disease-causing, submitted by 8 submitters, and is linked to primary hyperoxaluria type 2.

*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 recessive |
| Age of onset (of this condition) | All ages |
| Prevalence | 1-9 / 1 000 000 (Germany) |
| Clinical trials | 5 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | GRHPR is a diagnostic-grade gene on 9 Genomics England panels |

**Commonly reported features of Primary hyperoxaluria** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Hyperoxaluria — Very frequent (99-80%)
- Calcium oxalate nephrolithiasis — Very frequent (99-80%)
- Nephrocalcinosis — Frequent (79-30%)
- Abnormality of the dentition — Frequent (79-30%)
- Retinopathy — Frequent (79-30%)
- Optic disc pallor — Frequent (79-30%)
- Optic atrophy — Frequent (79-30%)
- Hematuria — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0002836/index) · [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.Pro203fs |
| Coding change (HGVS c.) | c.608_609del |
| MANE Select transcript | [NM_012203](https://www.ncbi.nlm.nih.gov/nuccore/NM_012203) |
| dbSNP | [rs180177316](https://www.ncbi.nlm.nih.gov/snp/rs180177316/) |
| Variant type | Deletion |
| Location | chr9:37430520-37430521 (GRCh38) |
| ClinVar | [VCV204252](https://www.ncbi.nlm.nih.gov/clinvar/variation/204252/) |

**All HGVS expressions:** `NC_000009.11:g.37430517_37430518del`, `NC_000009.12:g.37430520_37430521del`, `NG_008135.1:g.12811_12812del`, `NM_012203.1:c.608_609del`, `NM_012203.2:c.608_609del`, `NM_012203.2:c.608_609delCT`

## 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 -2.923, GERP -3.67 — fast-evolving / accelerated position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.313, pLI 3.7191e-09. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 7 of 9**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 22.6**. 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** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.00223%** (eas) · FAF95 0.000429% · FAF99 0.000313% · 1/44,898 in the highest group · 12/1,613,538 alleles overall — very rare (popmax 0.00223%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.00223% | 44,898 |
| African / African-American | 0.00133% | 74,912 |
| European (non-Finnish) | 0.000848% | 117,954 |

*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}

Residue **203** lies in an α-helix.

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}

**Pathogenic/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-01-27.

**Submitter consensus:** conflicting (7 Pathogenic, 1 Likely pathogenic).

**Submission history:** 8 submissions (2014–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Clinical Biochemistry Laboratory, Health Services Laboratory | Pathogenic | no assertion criteria provided | research | 2014-11-27 |
| Counsyl | Pathogenic | no assertion criteria provided | clinical testing | 2016-11-07 |
| Natera, Inc. | Pathogenic | no assertion criteria provided | clinical testing | 2020-09-16 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Pathogenic | criteria provided, single submitter | clinical testing | 2021-06-17 |
| Fulgent Genetics, Fulgent Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2021-10-28 |
| Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Pathogenic | criteria provided, single submitter | clinical testing | 2024-09-19 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2023-12-25 |
| First Genomix Gene Laboratory, Genetic Diagnostics Department | Likely pathogenic | criteria provided, single submitter | clinical testing | 2025-01-27 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Primary hyperoxaluria, type II, not provided, none provided, OXALOSIS II, D-GLYCERATE DEHYDROGENASE DEFICIENCY, GLYCERIC ACIDURIA, GLYOXYLATE REDUCTASE/HYDROXYPYRUVATE REDUCTASE DEFICIENCY, Primary hyperoxaluria type 2.

## Similar variants {#similar}

Related GRHPR variant pages (same residue, condition, or type): [GRHPR c.206_214+11del](/variant/grhpr-c-206-214-plus-11del), [GRHPR c.735-2del](/variant/grhpr-c-735-minus-2del), [GRHPR p.Ala197fs](/variant/grhpr-p-ala197fs), [GRHPR p.Ala206fs](/variant/grhpr-p-ala206fs), [GRHPR p.Ala52fs](/variant/grhpr-p-ala52fs), [GRHPR p.Asp35fs](/variant/grhpr-p-asp35fs), [GRHPR p.Asp91fs](/variant/grhpr-p-asp91fs), [GRHPR p.Gln232fs](/variant/grhpr-p-gln232fs).

### 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 204252). 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.*