Is PC p.Arg453Gln (c.1358G>A) pathogenic?

PC p.Arg453Gln (c.1358G>A) is classified Uncertain significance in PC (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-06-11). AlphaMissense: likely pathogenic (0.8015); Very rare (popmax 0.000424%, nfe); Associated with pyruvate carboxylase deficiency disease.

What condition is associated with PC p.Arg453Gln (c.1358G>A)?

PC p.Arg453Gln (c.1358G>A) is associated with pyruvate carboxylase deficiency disease (ClinVar).

How common is PC p.Arg453Gln (c.1358G>A) in the general population?

PC p.Arg453Gln (c.1358G>A) is very rare (popmax 0.000424%, nfe) (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.Arg453Gln (c.1358G>A)?

AlphaMissense predicts likely pathogenic (score 0.8015) — an in-silico prediction, not a clinical call.

PC p.Arg453Gln

c.1358G>A · rs2495672122 · VCV2193075

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8015 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

pyruvate carboxylase deficiency disease

Computational evidence

Protein change
AlphaMissense	0.8015	likely pathogenic
REVEL	0.631	indeterminate
SaProt	LLR -10.63	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	Δ0.20	donor gain · deltas
Constraint at this position
Conservation	phyloP 7.5	GERP 2.2, 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

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000424% European (non-Finnish) · 5/1,178,852 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000373% 6/1,610,578 alleles · very rare exomes 6/1,458,508 · genomes 0/152,070 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,388
European (non-Finnish)grpmax	0.000424%	235,771

Remaining individuals 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: PC
Protein: p.Arg453Gln
Coding: c.1358G>A
MANE Select: NM_001040716
dbSNP: rs2495672122
Type: single nucleotide variant
Location: chr11:66863784 (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 453: the biotin carboxylation 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.Arg453Ter Pathogenic/Likely pathogenic ★★ 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
PC p.Ala812Asp Likely pathogenic ★★ same condition
PC p.Arg18Ter Pathogenic/Likely 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-arg453gln (accessed [today's date]).

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