Is OTC p.Lys46Arg (c.137A>G) pathogenic?

OTC p.Lys46Arg (c.137A>G) is classified Benign in OTC (ClinVar, Multiple submitters, 18 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.0896); Common (popmax 38.1%, afr) — too common for a highly-penetrant pathogenic allele; Associated with Inborn genetic diseases.

What condition is associated with OTC p.Lys46Arg (c.137A>G)?

OTC p.Lys46Arg (c.137A>G) is associated with Inborn genetic diseases, ornithine carbamoyltransferase deficiency (ClinVar).

What do computational predictors say about OTC p.Lys46Arg (c.137A>G)?

AlphaMissense predicts likely benign (score 0.0896) — an in-silico prediction, not a clinical call.

OTC p.Lys46Arg

Q: How common is OTC p.Lys46Arg (c.137A>G) in the general population?

OTC p.Lys46Arg (c.137A>G) is common (popmax 38.1%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.137A>G · rs1800321 · VCV10994

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 18 submitters

AlphaMissense

likely benign

0.0896 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 38.1%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

ClinGen expert panel — Urea Cycle Disorders VCEP

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

BA1

Curation rationale (ClinGen, verbatim)

The NM_000531.6:c.137A>G (p.Lys46Arg) is a missense OTC variant in exon 2. The MAF >5% in all populations except in East Asians with more than one hundred thousand combined homo- and hemizygotes (BA1). In summary, this variant meets the criteria to be classified as benign 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.

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

Computational evidence

Protein change
AlphaMissense	0.0896	likely benign
REVEL	0.407	indeterminate
SaProt	LLR -7.07	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8	GERP 2.1, phastCons 1
Regional constraint	o/e 0.75	unconstrained · MANE · 68 kb · p 3.9e-05 · regional, not allelic
Overall
CADD	19.29	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 38.1% African / African-American · 21,543/56,509 alleles

Filtering AF 37.7% ClinGen BA1/BS1 input FAF95, joint · FAF99 37.5%

Overall 22.1% 264,991/1,200,554 alleles · common exomes 236,649/1,089,911 · genomes 28,342/110,643 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	38.8%	3
African / African-Americangrpmax	38.1%	3
Ashkenazi Jewishnot grpmax-eligible	29.3%	3
Middle Eastern	28.1%	4
European (non-Finnish)	23.4%	4
Remaining individualsnot grpmax-eligible	22.2%	5
Finnishnot grpmax-eligible	16.9%	6
Admixed American	13.6%	7
South Asian	5.37%	19
East Asian	0.0533%	1,875

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Lys46Arg
Coding: c.137A>G
MANE Select: NM_000531
dbSNP: rs1800321
Type: single nucleotide variant
Location: chrX:38367350 (GRCh38)
Structure: AlphaFold pLDDT 91.94 · 4 PDB
Residue 46: an α-helix; a UniProt-annotated variant site (in)

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: ornithine carbamoyltransferase deficiency

Similar variants

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
OTC c.663+2T>C 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-lys46arg (accessed [today's date]).

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