Is PC p.Pro536Leu (c.1607C>T) pathogenic?

PC p.Pro536Leu (c.1607C>T) is classified Conflicting classifications of pathogenicity in PC (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-08-14). AlphaMissense: likely benign (0.0699); Ultra-rare (popmax 0.0133%, amr); Associated with pyruvate carboxylase deficiency disease.

What condition is associated with PC p.Pro536Leu (c.1607C>T)?

PC p.Pro536Leu (c.1607C>T) is associated with pyruvate carboxylase deficiency disease (ClinVar).

How common is PC p.Pro536Leu (c.1607C>T) in the general population?

PC p.Pro536Leu (c.1607C>T) is ultra-rare (popmax 0.0133%, amr) (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.Pro536Leu (c.1607C>T)?

AlphaMissense predicts likely benign (score 0.0699) — an in-silico prediction, not a clinical call.

PC p.Pro536Leu

c.1607C>T · rs751657066 · VCV634557

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0699 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0133%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

pyruvate carboxylase deficiency disease

Computational evidence

Protein change
AlphaMissense	0.0699	likely benign
REVEL	0.262	benign-leaning
SaProt	LLR -8.55	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.50 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.4	GERP 0.9, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 23 kb · p 3.1e-25 · regional, not allelic
Overall
CADD	23.2	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 0.0133% Admixed American · 8/59,982 alleles

Filtering AF 0.00662% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00483%

Overall 0.0026% 42/1,613,496 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0133%	7,498
African / African-American	0.00801%	12,485
European (non-Finnish)	0.00229%	43,692
South Asian	0.0011%	91,072

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.Pro536Leu
Coding: c.1607C>T
MANE Select: NM_001040716
dbSNP: rs751657066
Type: single nucleotide variant
Location: chr11:66852657 (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 536: 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.Pro536= Benign/Likely benign ★★ 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-pro536leu (accessed [today's date]).

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