Is PLG p.Arg490= (c.1468C>A) pathogenic?

PLG p.Arg490= (c.1468C>A) is classified Likely benign in PLG (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-02-06). Ultra-rare (popmax 0.0414%, afr); Associated with angioedema, hereditary, 4.

What condition is associated with PLG p.Arg490= (c.1468C>A)?

PLG p.Arg490= (c.1468C>A) is associated with angioedema, hereditary, 4, hypoplasminogenemia (ClinVar).

How common is PLG p.Arg490= (c.1468C>A) in the general population?

PLG p.Arg490= (c.1468C>A) is ultra-rare (popmax 0.0414%, afr) (gnomAD).

PLG p.Arg490=

c.1468C>A · rs367707054 · VCV733902

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0414%, afr)

Conditions

angioedema, hereditary, 4

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>T here scores Δ0.27 · evaluated, not missing
Constraint at this position
Conservation	phyloP 2.5	GERP -0.66, phastCons 0.99
Overall
CADD	3.345	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0414% African / African-American · 31/74,830 alleles

Filtering AF 0.03% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.026%

Overall 0.00198% 32/1,613,722 alleles · ultra-rare exomes 20/1,461,768 · genomes 12/151,954 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0414%	2,414
Remaining individualsnot grpmax-eligible	0.0016%	62,474

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: PLG
Protein: p.Arg490=
Coding: c.1468C>A
MANE Select: NM_000301
dbSNP: rs367707054
Type: single nucleotide variant
Location: chr6:160731774 (GRCh38)
Gene constraint: LOEUF 0.559 · pLI 0.17 (gnomAD)
Structure: AlphaFold pLDDT 83.53 · 49 PDB
Residue 490: the kringle 5 domain

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

Disease context

angioedema, hereditary, 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hypoplasminogenemia

Similar variants

PLG p.Arg490Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
PLG p.Arg490Ter Pathogenic ★ same residue
PLG p.Lys330Glu Pathogenic ★★ ⚠ same condition
PLG p.Lys38Glu Pathogenic/Likely pathogenic ★★ ⚠ same condition
PLG c.669-3C>G Uncertain significance ★★ same condition
PLG p.Ala216Thr Uncertain significance ★★ ⚠ same condition
PLG p.Ala494Glu Uncertain significance ★★ ⚠ same condition
PLG p.Ala507Val 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/plg-p-arg490 (accessed [today's date]).

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