Is PLG p.Arg427= (c.1281G>A) pathogenic?

PLG p.Arg427= (c.1281G>A) is classified Benign/Likely benign in PLG (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-01-27). Rare (popmax 0.463%, nfe); Associated with hypoplasminogenemia.

What condition is associated with PLG p.Arg427= (c.1281G>A)?

PLG p.Arg427= (c.1281G>A) is associated with hypoplasminogenemia, angioedema, hereditary, 4 (ClinVar).

How common is PLG p.Arg427= (c.1281G>A) in the general population?

PLG p.Arg427= (c.1281G>A) is rare (popmax 0.463%, nfe) (gnomAD).

How is Hypoplasminogenemia inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

PLG p.Arg427=

c.1281G>A · rs149909079 · VCV788861

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

rare (popmax 0.463%, nfe)

Conditions

hypoplasminogenemia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.8	GERP -1.4, phastCons 1
Overall
CADD	10.3	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.463% European (non-Finnish) · 5,458/1,179,886 alleles

Filtering AF 0.452% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.448%

Overall 0.419% 6,768/1,613,986 alleles · rare exomes 6,216/1,461,678 · genomes 552/152,308 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	1.56%	64
European (non-Finnish)grpmax	0.463%	216
Finnishnot grpmax-eligible	0.44%	227
Remaining individualsnot grpmax-eligible	0.408%	245
Admixed American	0.337%	297
Middle Eastern	0.0661%	1,513
African / African-American	0.0653%	1,531
South Asian	0.0615%	1,626

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg427=
Coding: c.1281G>A
MANE Select: NM_000301
dbSNP: rs149909079
Type: single nucleotide variant
Location: chr6:160731075 (GRCh38)
Gene constraint: LOEUF 0.559 · pLI 0.17 (gnomAD)
Structure: AlphaFold pLDDT 83.53 · 49 PDB
Residue 427: the kringle 4 domain

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

Disease context

hypoplasminogenemia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: angioedema, hereditary, 4

For Hypoplasminogenemia (Orphanet):

Inheritance: Autosomal recessive
Onset: All ages
Prevalence: 1-9 / 1 000 000 (Europe)

Similar variants

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
PLG p.Ala675Val Uncertain significance ★★ ⚠ same condition
PLG p.Arg172Gly 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-arg427 (accessed [today's date]).

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