Is PC p.Arg77Trp (c.229C>T) pathogenic?

PC p.Arg77Trp (c.229C>T) is classified Uncertain significance in PC (ClinVar, Multiple submitters, 3 submitters; last evaluated 2022-07-02). AlphaMissense: likely pathogenic (0.9171); Very rare (popmax 0.000425%, nfe); Associated with Inborn genetic diseases.

What condition is associated with PC p.Arg77Trp (c.229C>T)?

PC p.Arg77Trp (c.229C>T) is associated with Inborn genetic diseases, pyruvate carboxylase deficiency disease (ClinVar).

How common is PC p.Arg77Trp (c.229C>T) in the general population?

PC p.Arg77Trp (c.229C>T) is very rare (popmax 0.000425%, nfe) (gnomAD).

What do computational predictors say about PC p.Arg77Trp (c.229C>T)?

AlphaMissense predicts likely pathogenic (score 0.9171) — an in-silico prediction, not a clinical call.

PC p.Arg77Trp

c.229C>T · rs928225163 · VCV812772

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9171 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000425%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9171	likely pathogenic
REVEL	0.837	moderately pathogenic-leaning
SaProt	LLR -13.66	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 9.7	GERP 0.6, 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 0.000425% European (non-Finnish) · 5/1,176,276 alleles

Filtering AF 0.000125% ClinGen BA1/BS1 input FAF95, joint · FAF99 9.1e-05%

Overall 0.000345% 5/1,450,974 alleles · very rare

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.Arg77Trp
Coding: c.229C>T
MANE Select: NM_001040716
dbSNP: rs928225163
Type: single nucleotide variant
Location: chr11:66871779 (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 77: the biotin carboxylation domain; a β-strand

Full PC 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: pyruvate carboxylase deficiency disease

Similar variants

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
PC p.Arg263Ter 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-arg77trp (accessed [today's date]).

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