Is PC p.Arg263Gln (c.788G>A) pathogenic?

PC p.Arg263Gln (c.788G>A) is classified Conflicting classifications of pathogenicity in PC (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2024-11-01). AlphaMissense: likely pathogenic (0.9806); Very rare (popmax 0.0022%, sas); Associated with pyruvate carboxylase deficiency disease.

What condition is associated with PC p.Arg263Gln (c.788G>A)?

PC p.Arg263Gln (c.788G>A) is associated with pyruvate carboxylase deficiency disease (ClinVar).

How common is PC p.Arg263Gln (c.788G>A) in the general population?

PC p.Arg263Gln (c.788G>A) is very rare (popmax 0.0022%, sas) (gnomAD).

How is Pyruvate carboxylase deficiency inherited?

Typically Autosomal recessive, Not applicable (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about PC p.Arg263Gln (c.788G>A)?

AlphaMissense predicts likely pathogenic (score 0.9806) — an in-silico prediction, not a clinical call.

PC p.Arg263Gln

c.788G>A · rs769177104 · VCV203921

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.9806 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

pyruvate carboxylase deficiency disease

Computational evidence

Protein change
AlphaMissense	0.9806	likely pathogenic
REVEL	0.944	strongly pathogenic-leaning
SaProt	LLR -16.80	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.3, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 23 kb · p 3.1e-25 · regional, not allelic
Overall
CADD	33.0	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 0.0022% South Asian · 2/91,088 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000136%

Overall 0.000248% 4/1,613,706 alleles · very rare exomes 4/1,461,424 · genomes 0/152,282 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0022%	45,544
African / African-American	0.00133%	75,026
European (non-Finnish)	8.47e-05%	1,180,008

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: PC
Protein: p.Arg263Gln
Coding: c.788G>A
MANE Select: NM_001040716
dbSNP: rs769177104
Type: single nucleotide variant
Location: chr11:66870417 (GRCh38)
Gene constraint: LOEUF 0.539 · pLI 0.07 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 90.53 · 10 PDB
Residue 263: the biotin carboxylation domain; the atp-grasp domain; a β-strand

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

Disease context

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

For Pyruvate carboxylase deficiency (Orphanet):

Inheritance: Autosomal recessive, Not applicable
Onset: Infancy, Neonatal
Prevalence: 1-9 / 1 000 000 (Europe)

Similar variants

PC p.Arg263Ter Pathogenic ★★ same residue
PC p.Arg263= Likely benign ★ same residue
PC p.Arg263Gly Uncertain significance ★ ⚠ same residue
PC c.1368+1G>A Likely pathogenic ★★ same condition
PC c.1826-1G>C Likely pathogenic ★★ same condition
PC c.1983-116C>T Likely pathogenic ★★ same condition
PC c.633+2T>C Likely pathogenic ★★ same condition
PC p.Ala610Thr 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/pc-p-arg263gln (accessed [today's date]).

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