Is OTC p.Ala254= (c.762G>T) pathogenic?

OTC p.Ala254= (c.762G>T) is classified Likely benign in OTC (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-06-09). Very rare (popmax 0.00296%, eas); Associated with ornithine carbamoyltransferase deficiency.

What condition is associated with OTC p.Ala254= (c.762G>T)?

OTC p.Ala254= (c.762G>T) is associated with ornithine carbamoyltransferase deficiency (ClinVar).

How common is OTC p.Ala254= (c.762G>T) in the general population?

OTC p.Ala254= (c.762G>T) is very rare (popmax 0.00296%, 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.Ala254=

c.762G>T · rs1388386866 · VCV509979

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00296%, eas)

Conditions

ornithine carbamoyltransferase deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.50	acceptor gain · deltas
Pangolin	Δ0.30	gain · loss 0.13 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP -0.72	GERP -4.4
Overall
CADD	12.28	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00296% East Asian · 1/33,729 alleles

Filtering AF 3.7e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.4e-05%

Overall 0.000248% 3/1,208,401 alleles · very rare exomes 1/1,096,950 · genomes 2/111,451 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00296%	33,729
European (non-Finnish)	0.000224%	447,035

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.Ala254=
Coding: c.762G>T
MANE Select: NM_000531
dbSNP: rs1388386866
Type: single nucleotide variant
Location: chrX:38408920 (GRCh38)
Structure: AlphaFold pLDDT 91.94 · 4 PDB
Residue 254: an α-helix

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.Ala254Val Uncertain significance ★★ 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
OTC c.663+1G>T 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-ala254 (accessed [today's date]).

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