# NM_000531.6(OTC):c.621C>T (p.Ser207=)

https://sugi.bio/variant/otc-p-ser207

## Summary

**OTC p.Ser207= (c.621C>T)** is classified **Benign/Likely benign** in OTC (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-01-30). Ultra-rare (popmax 0.0889%, eas); Associated with ornithine carbamoyltransferase deficiency.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs72558415 · 6 submitters · 1 linked condition · ultra-rare (popmax 0.0889%, eas)

## For patients & families {#patients}

This is a change in the OTC gene that is classified as benign/likely benign — not considered disease-causing, submitted by 6 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.Ser207= |
| Coding change (HGVS c.) | c.621C>T |
| MANE Select transcript | [NM_000531](https://www.ncbi.nlm.nih.gov/nuccore/NM_000531) |
| dbSNP | [rs72558415](https://www.ncbi.nlm.nih.gov/snp/rs72558415/) |
| Variant type | single nucleotide variant |
| Location | chrX:38403698-38403698 (GRCh38) |
| ClinVar | [VCV368259](https://www.ncbi.nlm.nih.gov/clinvar/variation/368259/) |

**All HGVS expressions:** `LRG_846:g.56216C>T`, `LRG_846t1:c.621C>T`, `NC_000023.10:g.38262951C>T`, `NC_000023.11:g.38403698C>T`, `NG_008471.1:g.56216C>T`, `NM_000531.6:c.621C>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 (below), not from a missing predictor score.
- Conservation: phyloP 0.297, GERP -4.43, phastCons 0.997 — weakly conserved position
- CADD: **PHRED 4.262**. 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** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.0889%** (eas) · FAF95 0.0639% · FAF99 0.0555% · 30/33,752 in the highest group · 46/1,206,826 alleles overall — ultra-rare (popmax 0.0889%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.0889% | 1,125 |
| Admixed American | 0.0219% | 4,573 |
| Remaining individuals (not grpmax-eligible) | 0.00421% | 23,759 |
| South Asian | 0.00352% | 28,370 |
| European (non-Finnish) | 0.000224% | 446,148 |

*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 **207** lies in a UniProt-annotated variant site (in otcd; neonatal); a turn.

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}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-01-30.

**Submitter consensus:** conflicting (4 Benign, 2 Likely benign).

**Submission history:** 6 submissions (2017–2026); classifications have differed over time.

**ClinGen expert panel:** Benign — Urea Cycle Disorders VCEP (ornithine carbamoyltransferase deficiency). *Expert-panel curated (ACMG); the highest ClinVar review tier.*
**Applied ACMG criteria (met):** `BP7`, `BA1`.
*Considered but not met:* `PM2`, `PM1`, `PP4`.
Inheritance: X-linked inheritance (recessive (HP:0001419)).

> **Curation rationale (ClinGen, verbatim):** The NM_000531.6: c.621C>T (p.Ser207=) variant is a synonymous (silent) variant that is not predicted by SpliceAI to impact splicing (BP4, BP7). The highest population minor allele frequency in gnomAD v4.1.0 is 0.0008888 (30/33752 alleles) in the East Asian population and there are 13 hemizygotes across all populations, which is higher than the ClinGen OTC VCEP threshold (≥10 male hemizygotes) for BA1, and therefore meets this criterion (BA1). In summary, this variant meets the criteria to be classified as Benign for X-linked ornithine carbamoyltransferase deficiency. ACMG/AMP criteria met, as specified by the ClinGen Urea Cycle Disorders VCEP (OTC specifications version 1.0.0): BA1, BP4, BP7.
*Source: https://cspec.clinicalgenome.org/cspec/ui/svi/affiliation/50100 · approved 2026-05-21 · [ClinGen Evidence Repository](https://erepo.genome.network/evrepo/ui/classification/412b662e-dec2-45af-ba81-64507e94994c).*
*These are ClinGen's applied codes, reported verbatim — Sugi Variant does not re-tally or combine them into its own classification.*

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| All of Us Research Program, National Institutes of Health | Benign | criteria provided, single submitter | clinical testing | 2024-01-08 |
| Color Diagnostics, LLC DBA Color Health | Benign | criteria provided, single submitter | clinical testing | 2022-04-21 |
| Illumina Laboratory Services, Illumina | Likely benign | criteria provided, single submitter | clinical testing | 2017-04-28 |
| Ambry Genetics | Benign | criteria provided, single submitter | clinical testing | 2017-01-31 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-01-30 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-06-27 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Ornithine carbamoyltransferase deficiency, Inborn genetic diseases, not specified, Ornithine Carbamoyltransferase Deficiency Disease, ORNITHINE TRANSCARBAMYLASE DEFICIENCY, ORNITHINE TRANSCARBAMYLASE DEFICIENCY, HYPERAMMONEMIA DUE TO, OTC DEFICIENCY, AllHighlyPenetrant.

## Same-residue context {#hotspot}

Residue **207** carries **2 other pathogenic ClinVar variants** — a recurrently-mutated position: [OTC p.Ser207Asn](/variant/otc-p-ser207asn), [OTC p.Ser207Arg](/variant/otc-p-ser207arg). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related OTC variant pages (same residue, condition, or type): [OTC p.Ser207Arg](/variant/otc-p-ser207arg), [OTC p.Ser207Asn](/variant/otc-p-ser207asn), [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), [OTC c.540+1G>T](/variant/otc-c-540-plus-1g-t), [OTC c.540+265G>A](/variant/otc-c-540-plus-265g-a).

### 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 368259). 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.*