Is PLG p.Arg445Ser (c.1335G>T) pathogenic?

PLG p.Arg445Ser (c.1335G>T) is classified Conflicting classifications of pathogenicity in PLG (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-02-03). AlphaMissense: likely pathogenic (0.8007); Rare (popmax 0.33%, sas); Associated with hypoplasminogenemia.

What condition is associated with PLG p.Arg445Ser (c.1335G>T)?

PLG p.Arg445Ser (c.1335G>T) is associated with hypoplasminogenemia, angioedema, hereditary, 4 (ClinVar).

How common is PLG p.Arg445Ser (c.1335G>T) in the general population?

PLG p.Arg445Ser (c.1335G>T) is rare (popmax 0.33%, sas) (gnomAD).

How is Hypoplasminogenemia inherited?

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

What do computational predictors say about PLG p.Arg445Ser (c.1335G>T)?

AlphaMissense predicts likely pathogenic (score 0.8007) — an in-silico prediction, not a clinical call.

PLG p.Arg445Ser

c.1335G>T · rs371661937 · VCV2081074

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8007 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.33%, sas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

hypoplasminogenemia

Computational evidence

Protein change
AlphaMissense	0.8007	likely pathogenic
REVEL	0.474	indeterminate
SaProt	LLR -10.87	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.28	GERP -3.8, phastCons 0.86
Regional constraint	o/e 0.92	unconstrained · MANE · 50 kb · p 0.011 · regional, not allelic
Overall
CADD	19.21	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 0.33% South Asian · 301/91,082 alleles

Filtering AF 0.3% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.288%

Overall 0.0209% 337/1,614,046 alleles · rare exomes 320/1,461,744 · genomes 17/152,302 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.33%	303
Middle Eastern	0.0661%	1,513
Remaining individualsnot grpmax-eligible	0.024%	4,167
East Asian	0.00223%	44,874
Admixed American	0.00167%	60,016
European (non-Finnish)	0.00127%	78,662

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.Arg445Ser
Coding: c.1335G>T
MANE Select: NM_000301
dbSNP: rs371661937
Type: single nucleotide variant
Location: chr6:160731129 (GRCh38)
Gene constraint: LOEUF 0.559 · pLI 0.17 (gnomAD)
Structure: AlphaFold pLDDT 83.53 · 49 PDB
Residue 445: the kringle 4 domain; a binding site

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.Arg445Met Uncertain significance ★★ ⚠ 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
PLG p.Ala675Val 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-arg445ser (accessed [today's date]).

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