Is PC p.His506= (c.1518T>C) pathogenic?

PC p.His506= (c.1518T>C) is classified Likely benign in PC (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-19). Very rare (popmax 0.00354%, amr); Associated with pyruvate carboxylase deficiency disease.

What condition is associated with PC p.His506= (c.1518T>C)?

PC p.His506= (c.1518T>C) is associated with pyruvate carboxylase deficiency disease (ClinVar).

How common is PC p.His506= (c.1518T>C) in the general population?

PC p.His506= (c.1518T>C) is very rare (popmax 0.00354%, amr) (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.His506=

c.1518T>C · rs781319350 · VCV1123379

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00354%, amr)

Conditions

pyruvate carboxylase deficiency disease

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>C here scores Δ0.47 · evaluated, not missing
Constraint at this position
Conservation	phyloP -4.6	GERP -4
Overall
CADD	0.477	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00354% Admixed American · 2/56,550 alleles

Filtering AF 0.000587% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00022%

Overall 0.000512% 8/1,563,210 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00354%	28,275
South Asian	0.0012%	83,372
European (non-Finnish)	0.000435%	230,075

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.His506=
Coding: c.1518T>C
MANE Select: NM_001040716
dbSNP: rs781319350
Type: single nucleotide variant
Location: chr11:66852832 (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 506: 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.His506Pro 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
PC p.Ala812Asp Likely pathogenic ★★ same condition
PC p.Arg18Ter 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-his506 (accessed [today's date]).

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