Is PC p.Pro530Leu (c.1589C>T) pathogenic?

PC p.Pro530Leu (c.1589C>T) is classified Conflicting classifications of pathogenicity in PC (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2026-01-28). AlphaMissense: likely pathogenic (0.5729); Very rare (popmax 0.00545%, nfe); Associated with pyruvate carboxylase deficiency disease.

What condition is associated with PC p.Pro530Leu (c.1589C>T)?

PC p.Pro530Leu (c.1589C>T) is associated with pyruvate carboxylase deficiency disease (ClinVar).

How common is PC p.Pro530Leu (c.1589C>T) in the general population?

PC p.Pro530Leu (c.1589C>T) is very rare (popmax 0.00545%, nfe) (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.Pro530Leu (c.1589C>T)?

AlphaMissense predicts likely pathogenic (score 0.5729) — an in-silico prediction, not a clinical call.

PC p.Pro530Leu

c.1589C>T · rs370248734 · VCV792985

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.5729 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00545%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

pyruvate carboxylase deficiency disease

Computational evidence

Protein change
AlphaMissense	0.5729	likely pathogenic
REVEL	0.746	pathogenic-leaning
SaProt	LLR -12.85	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 12	GERP 2, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 23 kb · p 3.1e-25 · regional, not allelic
Overall
CADD	28.4	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 0.00545% European (non-Finnish) · 64/1,174,186 alleles

Filtering AF 0.00437% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00397%

Overall 0.0089% 143/1,606,124 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.242%	413
Remaining individualsnot grpmax-eligible	0.00967%	10,342
European (non-Finnish)grpmax	0.00545%	18,347
Admixed American	0.00168%	59,672
African / African-American	0.00134%	74,806

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro530Leu
Coding: c.1589C>T
MANE Select: NM_001040716
dbSNP: rs370248734
Type: single nucleotide variant
Location: chr11:66852761 (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 530: 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 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-pro530leu (accessed [today's date]).

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