Is OTC p.Thr49= (c.147C>T) pathogenic?

OTC p.Thr49= (c.147C>T) is classified Benign/Likely benign in OTC (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-01-26). Very rare (popmax 0.00594%, eas); Associated with ornithine carbamoyltransferase deficiency.

What condition is associated with OTC p.Thr49= (c.147C>T)?

OTC p.Thr49= (c.147C>T) is associated with ornithine carbamoyltransferase deficiency (ClinVar).

How common is OTC p.Thr49= (c.147C>T) in the general population?

OTC p.Thr49= (c.147C>T) is very rare (popmax 0.00594%, 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.Thr49=

c.147C>T · rs144153859 · VCV1166654

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00594%, eas)

Conditions

ornithine carbamoyltransferase deficiency

ClinGen expert panel — Urea Cycle Disorders VCEP

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

BP7 BP4 BA1

Curation rationale (ClinGen, verbatim)

The NM_000531.6:c.147C>T (p.Thr49=) variant in OTC is a synonymous variant in exon 2 of the OTC gene. There are 10 hemizygous males in gnomAD v.4.1.0. This variant being observed in ≥10 (female) homozygotes or (male) hemizygotes in the most current version of gnomAD available at the time of curation (v.4.1.0), The NM_000531.6:c.147C>T (p.Thr49=) meets BP4 (Splice AI predicts no impact of the variant on splicing) (BP4, BP7) In summary, this variant meets the criteria to be classified as a benign variant for OTC deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Urea Cycle Disorders Variant Curation Expert Panel (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 0.61	GERP -3, phastCons 0.93
Overall
CADD	4.396	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00594% East Asian · 2/33,694 alleles

Filtering AF 0.00107% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000867%

Overall 0.002% 24/1,197,152 alleles · very rare exomes 22/1,086,146 · genomes 2/111,006 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00594%	16,847
Admixed American	0.00439%	22,794
Remaining individualsnot grpmax-eligible	0.00423%	23,617
African / African-American	0.00353%	28,343
European (non-Finnish)	0.00181%	55,257

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.Thr49=
Coding: c.147C>T
MANE Select: NM_000531
dbSNP: rs144153859
Type: single nucleotide variant
Location: chrX:38367360 (GRCh38)
Structure: AlphaFold pLDDT 91.94 · 4 PDB

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.Thr49Ile Uncertain significance ★ ⚠ same residue
OTC p.Thr49Pro Uncertain significance ★ ⚠ same residue
OTC p.Thr49Ser 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

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-thr49 (accessed [today's date]).

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