Is PC p.Val731Met (c.2191G>A) pathogenic?

PC p.Val731Met (c.2191G>A) is classified Uncertain significance in PC (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-18). AlphaMissense: likely benign (0.2662); Very rare (popmax 0.00186%, nfe); Associated with Inborn genetic diseases.

What condition is associated with PC p.Val731Met (c.2191G>A)?

PC p.Val731Met (c.2191G>A) is associated with Inborn genetic diseases (ClinVar).

How common is PC p.Val731Met (c.2191G>A) in the general population?

PC p.Val731Met (c.2191G>A) is very rare (popmax 0.00186%, nfe) (gnomAD).

What do computational predictors say about PC p.Val731Met (c.2191G>A)?

AlphaMissense predicts likely benign (score 0.2662) — an in-silico prediction, not a clinical call.

PC p.Val731Met

c.2191G>A · VCV4626998

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2662 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00186%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2662	likely benign
REVEL	0.831	moderately pathogenic-leaning
SaProt	LLR -13.02	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.4, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 23 kb · p 3.1e-25 · regional, not allelic
Overall
CADD	26.4	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 0.00186% European (non-Finnish) · 22/1,180,022 alleles

Filtering AF 0.00122% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.00149% 24/1,613,106 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00186%	53,637
Remaining individualsnot grpmax-eligible	0.0016%	62,472
African / African-American	0.00133%	74,932

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.Val731Met
Coding: c.2191G>A
MANE Select: NM_001040716
Type: single nucleotide variant
Location: chr11:66851072 (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 731: an α-helix; the pyruvate carboxyltransferase domain

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

Similar variants

PC p.Val731Ala Uncertain significance ★ ⚠ same residue
PC p.Val731= Likely benign ★ same residue
PC p.Ala280Thr Uncertain significance ★★ ⚠ same condition
PC p.Ala431Gly Uncertain significance ★★ ⚠ same condition
PC p.Arg31His Uncertain significance ★★ ⚠ same condition
PC p.Arg385Cys Uncertain significance ★★ ⚠ same condition
PC p.Arg393Cys Uncertain significance ★★ ⚠ same condition
PC p.Arg77Trp Uncertain significance ★★ ⚠ 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-val731met (accessed [today's date]).

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