Is PC p.Ser719fs (c.2156_2159del) pathogenic?

PC p.Ser719fs (c.21562159del) is classified Pathogenic in PC (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-11). Very rare (popmax 0.000169%, nfe); Associated with pyruvate carboxylase deficiency disease.

What condition is associated with PC p.Ser719fs (c.2156_2159del)?

PC p.Ser719fs (c.2156_2159del) is associated with pyruvate carboxylase deficiency disease (ClinVar).

How common is PC p.Ser719fs (c.2156_2159del) in the general population?

PC p.Ser719fs (c.2156_2159del) is very rare (popmax 0.000169%, nfe) (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.Ser719fs

c.2156_2159del · rs2135803326 · VCV1076206

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

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 17 of 23
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 2.1	GERP 1.4, phastCons 1

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000169% European (non-Finnish) · 2/1,179,972 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,460,956 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.Ser719fs
Coding: c.2156_2159del
MANE Select: NM_001040716
dbSNP: rs2135803326
Type: Deletion
Location: chr11:66851104 (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 719: 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.Ser719= 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
PC p.Lys1130fs 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-ser719fs (accessed [today's date]).

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