Is PGC p.Val189Met (c.565G>A) pathogenic?

PGC p.Val189Met (c.565G>A) is classified Uncertain significance in PGC (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-15). AlphaMissense: likely benign (0.1681); Ultra-rare (popmax 0.028%, afr).

How common is PGC p.Val189Met (c.565G>A) in the general population?

PGC p.Val189Met (c.565G>A) is ultra-rare (popmax 0.028%, afr) (gnomAD).

What do computational predictors say about PGC p.Val189Met (c.565G>A)?

AlphaMissense predicts likely benign (score 0.1681) — an in-silico prediction, not a clinical call.

PGC p.Val189Met

c.565G>A · rs372664007 · VCV2356023

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1681 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.028%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1681	likely benign
REVEL	0.187	benign-leaning
SaProt	LLR -6.04	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -6.4	GERP -5.1
Regional constraint	o/e 0.97	unconstrained · MANE · 10 kb · p 0.46 · regional, not allelic
Overall
CADD	0.662	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 0.028% African / African-American · 21/75,020 alleles

Filtering AF 0.0187% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0157%

Overall 0.00328% 53/1,614,152 alleles · ultra-rare exomes 33/1,461,870 · genomes 20/152,282 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.028%	3,572
Admixed American	0.02%	5,002
Middle Eastern	0.0165%	6,062
Remaining individualsnot grpmax-eligible	0.0064%	15,626
European (non-Finnish)	0.00127%	78,668

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: PGC
Protein: p.Val189Met
Coding: c.565G>A
MANE Select: NM_002630
dbSNP: rs372664007
Type: single nucleotide variant
Location: chr6:41742372 (GRCh38)
Gene constraint: LOEUF 0.991 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.60 · 2 PDB
Residue 189: the peptidase a1 domain; an α-helix

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

Similar variants

PGC p.Ala174Val Uncertain significance ★ ⚠ same type
PGC p.Ala183Thr Uncertain significance ★ ⚠ same type
PGC p.Ala186Val Uncertain significance ★ ⚠ same type
PGC p.Ala224Pro Uncertain significance ★ ⚠ same type
PGC p.Ala242Val Uncertain significance ★ ⚠ same type
PGC p.Ala388Thr Uncertain significance ★ ⚠ same type
PGC p.Ala67Gly Uncertain significance ★ ⚠ same type
PGC p.Ala67Val Uncertain significance ★ ⚠ same type

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/pgc-p-val189met (accessed [today's date]).

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