Is PC p.Thr1003fs (c.3008del) pathogenic?

PC p.Thr1003fs (c.3008del) is classified Pathogenic in PC (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-14). Very rare (popmax 0.00133%, afr); Associated with pyruvate carboxylase deficiency disease.

What condition is associated with PC p.Thr1003fs (c.3008del)?

PC p.Thr1003fs (c.3008del) is associated with pyruvate carboxylase deficiency disease (ClinVar).

How common is PC p.Thr1003fs (c.3008del) in the general population?

PC p.Thr1003fs (c.3008del) is very rare (popmax 0.00133%, afr) (gnomAD).

How is Pyruvate carboxylase deficiency inherited?

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

PC p.Thr1003fs

c.3008del · rs2495404851 · VCV2428441

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Conditions

pyruvate carboxylase deficiency disease

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 21 of 23
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.59	GERP -4.3, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/75,054 alleles

Overall 6.2e-05% 1/1,614,194 alleles · very rare exomes 1/1,461,866 · genomes 0/152,328 · joint denominator

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.Thr1003fs
Coding: c.3008del
MANE Select: NM_001040716
dbSNP: rs2495404851
Type: Deletion
Location: chr11:66849750 (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 1003: a modified residue (phosphothreonine)

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.Thr1003Met Uncertain significance ★★ ⚠ same residue
PC p.Thr1003= Likely benign ★ same residue
PC c.2473+2_2473+5del Pathogenic/Likely pathogenic ★★ same condition
PC p.Arg571fs Pathogenic/Likely pathogenic ★★ same condition
PC p.Cys752fs Pathogenic/Likely pathogenic ★★ same condition
PC p.Gly303fs Pathogenic/Likely pathogenic ★★ same condition
PC p.Leu1030fs Pathogenic/Likely pathogenic ★★ same condition
PC p.Leu1137fs 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-thr1003fs (accessed [today's date]).

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