Is PC p.Val699Met (c.2095G>A) pathogenic?

PC p.Val699Met (c.2095G>A) is classified Uncertain significance in PC (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-03). AlphaMissense: ambiguous (0.5513); Ultra-rare (popmax 0.0626%, sas); Associated with Inborn genetic diseases.

What condition is associated with PC p.Val699Met (c.2095G>A)?

PC p.Val699Met (c.2095G>A) is associated with Inborn genetic diseases (ClinVar).

How common is PC p.Val699Met (c.2095G>A) in the general population?

PC p.Val699Met (c.2095G>A) is ultra-rare (popmax 0.0626%, sas) (gnomAD).

What do computational predictors say about PC p.Val699Met (c.2095G>A)?

AlphaMissense predicts ambiguous (score 0.5513) — an in-silico prediction, not a clinical call.

PC p.Val699Met

c.2095G>A · rs760108147 · VCV242443

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5513 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0626%, sas)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5513	ambiguous
REVEL	0.839	moderately pathogenic-leaning
SaProt	LLR -12.97	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
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	28.2	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 0.0626% South Asian · 57/91,096 alleles

Filtering AF 0.0496% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0449%

Overall 0.00565% 91/1,611,992 alleles · ultra-rare exomes 84/1,459,750 · genomes 7/152,242 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0626%	1,598
African / African-American	0.00534%	18,735
European (non-Finnish)	0.00254%	39,334

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.Val699Met
Coding: c.2095G>A
MANE Select: NM_001040716
dbSNP: rs760108147
Type: single nucleotide variant
Location: chr11:66851168 (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 699: a β-strand; 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.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
PC p.Asp1067Asn Uncertain significance ★★ ⚠ same condition
PC p.Asp903Asn 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-val699met (accessed [today's date]).

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