# NM_000531.6(OTC):c.959G>C (p.Arg320Pro)

https://sugi.bio/variant/otc-p-arg320pro

## Summary

**OTC p.Arg320Pro (c.959G>C)** is classified **Pathogenic** in OTC (ClinVar, Single submitter, 2 submitters; last evaluated 2019-07-15). AlphaMissense: likely pathogenic (0.8481); Absent from gnomAD v4.1; Associated with ornithine carbamoyltransferase deficiency.

**At a glance:** Pathogenic · review: Single submitter · rsID rs72558474 · 2 submitters · 1 linked condition · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the OTC gene that is reported as disease-causing, but on limited review, submitted by 2 submitters, and is linked to ornithine carbamoyltransferase deficiency.

*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) | X-linked recessive |
| Age of onset (of this condition) | All ages |
| Prevalence | 1-9 / 100 000 (Europe) |
| Clinical trials | 27 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | OTC is a diagnostic-grade gene on 9 Genomics England panels |

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

- Hepatic failure — Very frequent (99-80%)
- Splenomegaly — Very frequent (99-80%)
- Hypoglycemia — Very frequent (99-80%)
- Hyperammonemia — Very frequent (99-80%)
- Aminoaciduria — Very frequent (99-80%)
- Seizure — Frequent (79-30%)
- Hypotonia — Frequent (79-30%)
- Lethargy — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0008391/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [OTC](https://sugi.bio/atlas/gene/OTC/) |
| Protein change (HGVS p.) | p.Arg320Pro |
| Coding change (HGVS c.) | c.959G>C |
| MANE Select transcript | [NM_000531](https://www.ncbi.nlm.nih.gov/nuccore/NM_000531) |
| dbSNP | [rs72558474](https://www.ncbi.nlm.nih.gov/snp/rs72558474/) |
| Variant type | single nucleotide variant |
| Location | chrX:38411953-38411953 (GRCh38) |
| ClinVar | [VCV935343](https://www.ncbi.nlm.nih.gov/clinvar/variation/935343/) |

**All HGVS expressions:** `LRG_846:g.64471G>C`, `LRG_846t1:c.959G>C`, `NC_000023.10:g.38271206G>C`, `NC_000023.11:g.38411953G>C`, `NG_008471.1:g.64471G>C`, `NM_000531.6:c.959G>C`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- AlphaMissense **likely pathogenic** (0.8481) — concordant with the pathogenic call
- REVEL 0.658 (pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -14.663 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 0.223, GERP -1.51 — weakly conserved position
- CADD: **PHRED 19.5**. 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 0.75** across the covering region of the MANE Select transcript (38,352,697–38,421,079), spanning 68,382 bp. Chi-square p 3.9e-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). 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. This allele is not in the release, so all four of its deltas are under 0.2. 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, and here that is proven rather than inferred: a different substitution at this very position, G>T, IS in the release and scores Δ0.26 donor loss, so SpliceAI evaluated this position and this allele was not among the ones that cleared the filter. *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: **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}

**OTC** population constraint: 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):

- **ornithine carbamoyltransferase deficiency** — Definitive (XL)

## Protein context {#protein}

Residue **320** lies in a UniProt-annotated variant site (in otcd).

AlphaFold model confidence (whole protein): pLDDT 91.94, 87% of residues very-high.

**4 experimental structure(s)** (PDB): [1C9Y](https://www.rcsb.org/structure/1C9Y), [1EP9](https://www.rcsb.org/structure/1EP9), [1FVO](https://www.rcsb.org/structure/1FVO), [1OTH](https://www.rcsb.org/structure/1OTH).

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

*Describes the biological roles of OTC (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:** OTC's established molecular role includes ornithine carbamoyltransferase activity. In Reactome, OTC is annotated in disease pathway(s) including **OTC leader sequence variants cause OTC deficiency**, **OTC main chain variants cause OTC deficiency**.

**Disease mechanism (Reactome):** OTC loss or alteration is curated in [OTC leader sequence variants cause OTC deficiency](https://reactome.org/content/detail/R-HSA-9956551), [OTC main chain variants cause OTC deficiency](https://reactome.org/content/detail/R-HSA-9956553).

### Pathways affected {#pathways}

OTC participates in **5 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [OTC leader sequence variants cause OTC deficiency](https://reactome.org/content/detail/R-HSA-9956551) | curated |
| ⚕ [OTC main chain variants cause OTC deficiency](https://reactome.org/content/detail/R-HSA-9956553) | curated |
| [Negative transcriptional regulation of urea cycle enzymes](https://reactome.org/content/detail/R-HSA-9988426) | curated |
| [Urea cycle](https://reactome.org/content/detail/R-HSA-70635) | curated |
| [Mitochondrial protein import](https://reactome.org/content/detail/R-HSA-1268020) | electronic |

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

**Molecular function:** ornithine carbamoyltransferase activity.

**Biological process:** urea cycle, L-ornithine catabolic process, L-citrulline biosynthetic process, ammonium homeostasis.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2019-07-15.

**Submitter consensus:** unanimous (2/2 Pathogenic).

**Submission history:** 2 submissions (2019); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Hainan Provincial Key Laboratory for Human Reproductive Medicine and Genetic Research | Pathogenic | no assertion criteria provided | clinical testing |  |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2019-07-15 |

## Associated conditions {#conditions}

[ornithine carbamoyltransferase deficiency](https://sugi.bio/atlas/disease/ornithine-carbamoyltransferase-deficiency/).

**Reported phenotype names (ClinVar):** Ornithine carbamoyltransferase deficiency, ORNITHINE TRANSCARBAMYLASE DEFICIENCY, ORNITHINE TRANSCARBAMYLASE DEFICIENCY, HYPERAMMONEMIA DUE TO, OTC DEFICIENCY, Ornithine Carbamoyltransferase Deficiency Disease.

## Same-residue context {#hotspot}

Residue **320** carries **2 other pathogenic ClinVar variants** — a recurrently-mutated position: [OTC p.Arg320Ter](/variant/otc-p-arg320ter), [OTC p.Arg320Leu](/variant/otc-p-arg320leu). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related OTC variant pages (same residue, condition, or type): [OTC p.Arg320Ter](/variant/otc-p-arg320ter), [OTC p.Arg320Gln](/variant/otc-p-arg320gln), [OTC p.Arg320Leu](/variant/otc-p-arg320leu), [OTC p.Arg320=](/variant/otc-p-arg320), [OTC c.298+2T>G](/variant/otc-c-298-plus-2t-g), [OTC c.299-1G>A](/variant/otc-c-299-minus-1g-a), [OTC c.386+1G>A](/variant/otc-c-386-plus-1g-a), [OTC c.540+1G>A](/variant/otc-c-540-plus-1g-a).

### 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 935343). 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.*