Is PC p.Pro538Leu (c.1613C>T) pathogenic?

PC p.Pro538Leu (c.1613C>T) is classified Uncertain significance in PC (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-08-29). AlphaMissense: likely benign (0.1263); Very rare (popmax 0.00333%, amr); Associated with Inborn genetic diseases.

What condition is associated with PC p.Pro538Leu (c.1613C>T)?

PC p.Pro538Leu (c.1613C>T) is associated with Inborn genetic diseases, pyruvate carboxylase deficiency disease (ClinVar).

How common is PC p.Pro538Leu (c.1613C>T) in the general population?

PC p.Pro538Leu (c.1613C>T) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about PC p.Pro538Leu (c.1613C>T)?

AlphaMissense predicts likely benign (score 0.1263) — an in-silico prediction, not a clinical call.

PC p.Pro538Leu

c.1613C>T · rs151174961 · VCV1303613

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1263 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1263	likely benign
REVEL	0.639	indeterminate
SaProt	LLR -9.61	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.64 · evaluated, not missing
Constraint at this position
Conservation	phyloP 6.5	GERP 2, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 23 kb · p 3.1e-25 · regional, not allelic
Overall
CADD	24.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00333% Admixed American · 2/59,980 alleles

Filtering AF 0.00223% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00198%

Overall 0.00279% 45/1,613,468 alleles · very rare exomes 44/1,461,268 · genomes 1/152,200 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	29,990
Remaining individualsnot grpmax-eligible	0.0032%	31,229
European (non-Finnish)	0.00305%	32,768
African / African-American	0.00267%	37,459
South Asian	0.0022%	45,538
Finnishnot grpmax-eligible	0.00156%	63,922

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.Pro538Leu
Coding: c.1613C>T
MANE Select: NM_001040716
dbSNP: rs151174961
Type: single nucleotide variant
Location: chr11:66852651 (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 538: an α-helix

Full PC gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: pyruvate carboxylase deficiency disease

Similar variants

PC p.Pro538= 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-pro538leu (accessed [today's date]).

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