Is PC p.Thr568Ala (c.1702A>G) pathogenic?

PC p.Thr568Ala (c.1702A>G) is classified Conflicting classifications of pathogenicity in PC (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-01-25). AlphaMissense: likely pathogenic (0.8998); Rare (popmax 0.639%, eas); Associated with pyruvate carboxylase deficiency disease.

What condition is associated with PC p.Thr568Ala (c.1702A>G)?

PC p.Thr568Ala (c.1702A>G) is associated with pyruvate carboxylase deficiency disease (ClinVar).

How common is PC p.Thr568Ala (c.1702A>G) in the general population?

PC p.Thr568Ala (c.1702A>G) is rare (popmax 0.639%, eas) (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.Thr568Ala (c.1702A>G)?

AlphaMissense predicts likely pathogenic (score 0.8998) — an in-silico prediction, not a clinical call.

PC p.Thr568Ala

c.1702A>G · rs199969388 · VCV305623

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.8998 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.639%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

pyruvate carboxylase deficiency disease

Computational evidence

Protein change
AlphaMissense	0.8998	likely pathogenic
REVEL	0.867	moderately pathogenic-leaning
SaProt	LLR -11.48	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 7.8	GERP 2, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 23 kb · p 3.1e-25 · regional, not allelic
Overall
CADD	23.8	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 0.639% East Asian · 287/44,884 alleles

Filtering AF 0.579% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.555%

Overall 0.019% 306/1,613,986 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.639%	156
Remaining individualsnot grpmax-eligible	0.0192%	5,209
South Asian	0.00549%	18,218
European (non-Finnish)	0.000169%	589,988

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.Thr568Ala
Coding: c.1702A>G
MANE Select: NM_001040716
dbSNP: rs199969388
Type: single nucleotide variant
Location: chr11:66852562 (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 568: the pyruvate carboxyltransferase domain

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.Thr568= Likely benign ★★ same residue
PC p.Thr568fs Pathogenic ★ same residue
PC p.Thr568Met 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-thr568ala (accessed [today's date]).

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