Is OTC p.Ser207= (c.621C>T) pathogenic?

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.

What condition is associated with OTC p.Ser207= (c.621C>T)?

OTC p.Ser207= (c.621C>T) is associated with ornithine carbamoyltransferase deficiency (ClinVar).

How common is OTC p.Ser207= (c.621C>T) in the general population?

OTC p.Ser207= (c.621C>T) is ultra-rare (popmax 0.0889%, eas) (gnomAD).

How is Ornithine transcarbamylase deficiency inherited?

Typically X-linked recessive (Orphanet). A genetic counselor can assess individual risk for a family.

OTC p.Ser207=

c.621C>T · rs72558415 · VCV368259

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0889%, eas)

Conditions

ornithine carbamoyltransferase deficiency

ClinGen expert panel — Urea Cycle Disorders VCEP

Benign for ornithine carbamoyltransferase deficiency. Applied ACMG criteria (verbatim):

BP7 BA1

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.

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.3	GERP -4.4, phastCons 1
Overall
CADD	4.262	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0889% East Asian · 30/33,752 alleles

Filtering AF 0.0639% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0555%

Overall 0.00381% 46/1,206,826 alleles · ultra-rare exomes 40/1,094,952 · genomes 6/111,874 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0889%	1,125
Admixed American	0.0219%	4,573
Remaining individualsnot grpmax-eligible	0.00421%	23,759
South Asian	0.00352%	28,370
European (non-Finnish)	0.000224%	446,148

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: OTC
Protein: p.Ser207=
Coding: c.621C>T
MANE Select: NM_000531
dbSNP: rs72558415
Type: single nucleotide variant
Location: chrX:38403698 (GRCh38)
Structure: AlphaFold pLDDT 91.94 · 4 PDB
Residue 207: a UniProt-annotated variant site (in otcd; neonatal); a turn

Full OTC gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

ornithine carbamoyltransferase deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Ornithine transcarbamylase deficiency (Orphanet):

Inheritance: X-linked recessive
Onset: All ages
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

OTC p.Ser207Arg Pathogenic/Likely pathogenic ★★ same residue
OTC p.Ser207Asn Pathogenic same residue
OTC c.298+2T>G Pathogenic ★★ same condition
OTC c.299-1G>A Likely pathogenic ★★ same condition
OTC c.386+1G>A Pathogenic ★★ same condition
OTC c.540+1G>A Pathogenic ★★ same condition
OTC c.540+1G>T Pathogenic ★★ same condition
OTC c.540+265G>A Pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/otc-p-ser207 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown