Is PC p.Arg147Cys (c.439C>T) pathogenic?

PC p.Arg147Cys (c.439C>T) is classified Uncertain significance in PC (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-02-24). AlphaMissense: likely benign (0.1208); Very rare (popmax 0.00659%, sas); Associated with pyruvate carboxylase deficiency disease.

What condition is associated with PC p.Arg147Cys (c.439C>T)?

PC p.Arg147Cys (c.439C>T) is associated with pyruvate carboxylase deficiency disease (ClinVar).

How common is PC p.Arg147Cys (c.439C>T) in the general population?

PC p.Arg147Cys (c.439C>T) is very rare (popmax 0.00659%, 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.Arg147Cys (c.439C>T)?

AlphaMissense predicts likely benign (score 0.1208) — an in-silico prediction, not a clinical call.

PC p.Arg147Cys

c.439C>T · rs529087425 · VCV2201087

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1208 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00659%, sas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

pyruvate carboxylase deficiency disease

Computational evidence

Protein change
AlphaMissense	0.1208	likely benign
REVEL	0.659	pathogenic-leaning
SaProt	LLR -13.39	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 23 kb · p 3.1e-25 · regional, not allelic
Overall
CADD	32.0	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 0.00659% South Asian · 6/91,086 alleles

Filtering AF 0.00286% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00195%

Overall 0.00124% 20/1,613,826 alleles · very rare exomes 18/1,461,516 · genomes 2/152,310 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00659%	15,181
East Asian	0.00223%	44,884
European (non-Finnish)	0.0011%	90,771

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.Arg147Cys
Coding: c.439C>T
MANE Select: NM_001040716
dbSNP: rs529087425
Type: single nucleotide variant
Location: chr11:66871363 (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 147: the biotin carboxylation domain; an α-helix

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.Arg147Gly Uncertain significance ★ ⚠ same residue
PC p.Arg147His Conflicting classifications of pathogenicity ★ ⚠ 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

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-arg147cys (accessed [today's date]).

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