# NM_016335.6(PRODH):c.1292G>A (p.Arg431His)

https://sugi.bio/variant/prodh-p-arg431his

## Summary

**PRODH p.Arg431His (c.1292G>A)** is classified **Conflicting classifications of pathogenicity** in PRODH (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2026-02-01). Common (popmax 14.7%, nfe) — too common for a highly-penetrant pathogenic allele; Associated with hyperprolinemia type 1.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs2904552 · 8 submitters · 2 linked conditions · common (popmax 14.7%, nfe) — too common for a highly-penetrant pathogenic allele

## For patients & families {#patients}

This is a change in the PRODH gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 8 submitters, and is linked to hyperprolinemia type 1.

*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 |
| Diagnostic panels | PRODH is a diagnostic-grade gene on 2 Genomics England panels |

**Commonly reported features of Hyperprolinemia type 1** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Proteinuria — Frequent (79-30%)
- Nephropathy — Frequent (79-30%)
- Prolinuria — Frequent (79-30%)
- Hyperprolinemia — Frequent (79-30%)
- Seizure — Occasional (29-5%)
- Schizophrenia — Occasional (29-5%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0024670/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [PRODH](https://sugi.bio/atlas/gene/PRODH/) |
| Protein change (HGVS p.) | p.Arg431His |
| Coding change (HGVS c.) | c.1292G>A |
| MANE Select transcript | [NM_016335](https://www.ncbi.nlm.nih.gov/nuccore/NM_016335) |
| dbSNP | [rs2904552](https://www.ncbi.nlm.nih.gov/snp/rs2904552/) |
| Variant type | single nucleotide variant |
| Location | chr22:18918451-18918451 (GRCh38) |
| ClinVar | [VCV4011](https://www.ncbi.nlm.nih.gov/clinvar/variation/4011/) |

**All HGVS expressions:** `NC_000022.10:g.18905964C>T`, `NC_000022.11:g.18918451C>T`, `NG_008226.3:g.23103G>A`, `NM_001195226.2:c.968G>A`, `NM_016335.6:c.1292G>A`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — common (popmax 14.7%, nfe) — 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 0.795, GERP 0.975, phastCons 0.999 — weakly conserved position
- CADD: **PHRED 19.82**. 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 0.12** across the covering region of the MANE Select transcript (18,913,178–18,936,287), spanning 23,109 bp — the region is depleted of missense variation. Chi-square p 1.7e-05. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **no splice effect predicted**. SpliceAI outputs four numbers per variant, not one: acceptor loss, donor loss, acceptor gain, donor gain (DS_AL / DS_DL / DS_AG / DS_DG). A loss score is an existing splice site weakened or destroyed; a gain score is a new site created or an existing one strengthened. The release publishes its own filter rule, which we read from the dataset rather than assume: an allele is reported only if the largest of its four deltas reaches 0.2. No allele at this position is in the release, so all four are under 0.2 for every alternate allele here. No figure is shown because none was read: the bound is deduced from that absence. It is a result, not a gap in our data, because the release scores every possible substitution across the transcripts it covers (Ensembl MANE v1.4) before it filters, so what survives for a gene is one continuous stretch. What is measured is that this position sits inside the stretch covered for PRODH (886 scored positions, the nearest 41 bases away); what is taken from the release's own description, rather than measured, is that coverage inside that stretch is continuous. On that, SpliceAI did score it. *ClinGen's SVI treats the largest of the four as evidence against a splicing effect at or below 0.1, where it may support BP4, and as uninformative between 0.1 and 0.2. We cannot tell which applies here, so these SpliceAI data support neither BP4 nor PP3; that is a statement about this evidence alone, not about the variant's other evidence.*
- Population frequency (gnomAD v4.1): grpmax **14.7%** (nfe) · FAF95 14.5% · FAF99 14.4% · 13,033/88,734 in the highest group · 17,585/174,084 alleles overall — common (popmax 14.7%, nfe) — too common for a highly-penetrant pathogenic allele.

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Amish (not grpmax-eligible) | 50% | 2 |
| European (non-Finnish) (grpmax) | 14.7% | 7 |
| Ashkenazi Jewish (not grpmax-eligible) | 13.7% | 7 |
| Remaining individuals (not grpmax-eligible) | 11% | 9 |
| Middle Eastern | 9.81% | 10 |
| Finnish (not grpmax-eligible) | 6.73% | 15 |
| Admixed American | 6.69% | 15 |
| South Asian | 5.15% | 19 |
| African / African-American | 3.07% | 33 |
| East Asian | 0.0627% | 1,594 |

Amish shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}

**PRODH** population constraint: ClinGen dosage — haploinsufficiency gene assoc. with recessive phenotype, 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):

- **hyperprolinemia type 1** — Definitive (AR)

## Protein context {#protein}

Residue **431** lies in a UniProt-annotated variant site (in hyrpro1; benign; moderate reduction of enzymatic activity).

AlphaFold model confidence (whole protein): pLDDT 85.29, 62% of residues very-high.

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

*Describes the biological roles of PRODH (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:** PRODH's established molecular role includes proline dehydrogenase activity.


### Pathways affected {#pathways}

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

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Proline catabolism](https://reactome.org/content/detail/R-HSA-70688) | curated |

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

**Molecular function:** proline dehydrogenase activity, oxidoreductase activity, acting on the CH-NH group of donors, quinone or similar compound as acceptor, FAD binding.

**Biological process:** regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2026-02-01.

**Submitter consensus:** conflicting (2 Uncertain significance, 2 Benign, 2 Likely benign, 1 Likely pathogenic, 1 Pathogenic, 1 risk factor).

**Submission history:** 9 submissions (2005–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Centre for Mendelian Genomics, University Medical Centre Ljubljana | Likely pathogenic | criteria provided, single submitter | clinical testing | 2019-05-13 |
| Blueprint Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-11-28 |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2005-03-01 |
| OMIM | risk factor | no assertion criteria provided | literature only | 2005-03-01 |
| MGZ Medical Genetics Center | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-04-29 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-02-01 |
| Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre | Likely benign | criteria provided, single submitter | clinical testing | 2024-03-26 |
| Department of Pathology and Laboratory Medicine, Sinai Health System | Likely benign | criteria provided, single submitter | research | 2023-01-31 |
| Laboratory of Genetics, Children's Clinical University Hospital Latvia | Benign | criteria provided, single submitter | clinical testing | 2025-02-16 |

## Associated conditions {#conditions}

[hyperprolinemia type 1](https://sugi.bio/atlas/disease/hyperprolinemia-type-1/), [schizophrenia 4](https://sugi.bio/atlas/disease/schizophrenia-4/).

**Reported phenotype names (ClinVar):** Proline dehydrogenase deficiency, Schizophrenia 4, not specified, not provided, Hyperprolinemia type 1, PROLINE OXIDASE DEFICIENCY, SCHIZOPHRENIA, SUSCEPTIBILITY TO, 4, SCHIZOPHRENIA SUSCEPTIBILITY LOCUS, CHROMOSOME 22q11-RELATED, AllHighlyPenetrant, none provided.

## Similar variants {#similar}

Related PRODH variant pages (same residue, condition, or type): [PRODH c.1104+2T>C](/variant/prodh-c-1104-plus-2t-c), [PRODH p.Gln59Ter](/variant/prodh-p-gln59ter), [PRODH p.Tyr412Ter](/variant/prodh-p-tyr412ter), [PRODH c.1427+4C>T](/variant/prodh-c-1427-plus-4c-t), [PRODH c.1615+1G>C](/variant/prodh-c-1615-plus-1g-c), [PRODH c.482+6G>A](/variant/prodh-c-482-plus-6g-a), [PRODH c.929+3G>A](/variant/prodh-c-929-plus-3g-a), [PRODH p.Ala140Thr](/variant/prodh-p-ala140thr).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 4011). 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.*