Is UPB1 p.Arg326= (c.976C>A) pathogenic?

UPB1 p.Arg326= (c.976C>A) is classified Benign/Likely benign in UPB1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-11-12). Low-frequency (popmax 1.38%, afr); Associated with beta-ureidopropionase deficiency.

What condition is associated with UPB1 p.Arg326= (c.976C>A)?

UPB1 p.Arg326= (c.976C>A) is associated with beta-ureidopropionase deficiency (ClinVar).

How common is UPB1 p.Arg326= (c.976C>A) in the general population?

UPB1 p.Arg326= (c.976C>A) is low-frequency (popmax 1.38%, afr) (gnomAD).

How is Beta-ureidopropionase deficiency inherited?

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

UPB1 p.Arg326=

c.976C>A · rs113975342 · VCV100164

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

low-frequency (popmax 1.38%, afr)

Conditions

beta-ureidopropionase deficiency

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 2.6	GERP 1.5, phastCons 1
Overall
CADD	10.17	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.38% African / African-American · 1,035/75,066 alleles

Filtering AF 1.31% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.28%

Overall 0.0742% 1,197/1,614,272 alleles · low-frequency exomes 630/1,461,890 · genomes 567/152,382 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.38%	73
Remaining individualsnot grpmax-eligible	0.126%	791
Middle Eastern	0.066%	1,516
Admixed American	0.0566%	1,766
South Asian	0.00768%	13,013
European (non-Finnish)	0.00322%	31,054

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: UPB1
Protein: p.Arg326=
Coding: c.976C>A
MANE Select: NM_016327
dbSNP: rs113975342
Type: single nucleotide variant
Location: chr22:24523678 (GRCh38)
Gene constraint: LOEUF 0.982 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 97.10 · 2 PDB
Residue 326: the cn hydrolase domain; a UniProt-annotated variant site (in upb1d; complete loss of activity; abolishes formation of higher oligomers)

Full UPB1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

beta-ureidopropionase deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Beta-ureidopropionase deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

UPB1 p.Arg326Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
UPB1 c.873+1G>A Pathogenic/Likely pathogenic ★★ same condition
UPB1 c.917-1G>A Pathogenic/Likely pathogenic ★★ same condition
UPB1 p.Asn345Ile Likely pathogenic ★★ same condition
UPB1 p.Gln118Ter Pathogenic ★★ same condition
UPB1 c.-27G>C Uncertain significance ★★ same condition
UPB1 p.Ala2Gly Uncertain significance ★★ ⚠ same condition
UPB1 p.Arg236Gln Uncertain significance ★★ ⚠ 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/upb1-p-arg326 (accessed [today's date]).

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