Is PLG p.Ser460Arg (c.1380T>A) pathogenic?

PLG p.Ser460Arg (c.1380T>A) is classified Benign in PLG (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-04-01). AlphaMissense: likely benign (0.1742); Common (popmax 10.2%, mid) — too common for a highly-penetrant pathogenic allele; Associated with angioedema, hereditary, 4.

What condition is associated with PLG p.Ser460Arg (c.1380T>A)?

PLG p.Ser460Arg (c.1380T>A) is associated with angioedema, hereditary, 4, hypoplasminogenemia (ClinVar).

What do computational predictors say about PLG p.Ser460Arg (c.1380T>A)?

AlphaMissense predicts likely benign (score 0.1742) — an in-silico prediction, not a clinical call.

PLG p.Ser460Arg

Q: How common is PLG p.Ser460Arg (c.1380T>A) in the general population?

PLG p.Ser460Arg (c.1380T>A) is common (popmax 10.2%, mid) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1380T>A · rs116573785 · VCV778275

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1742 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 10.2%, mid) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

angioedema, hereditary, 4

Computational evidence

Protein change
AlphaMissense	0.1742	likely benign
REVEL	0.02	moderately benign-leaning
SaProt	LLR -7.88	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 -4.8	GERP -1.9
Regional constraint	o/e 0.92	unconstrained · MANE · 50 kb · p 0.011 · regional, not allelic
Overall
CADD	0.046	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 10.2% Middle Eastern · 620/6,056 alleles

Filtering AF 9.57% ClinGen BA1/BS1 input FAF95, joint · FAF99 9.31%

Overall 0.373% 6,015/1,613,750 alleles · common exomes 4,048/1,461,828 · genomes 1,967/151,922 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	10.2%	10
African / African-American	4.12%	24
Remaining individualsnot grpmax-eligible	0.827%	121
Admixed American	0.617%	162
Ashkenazi Jewishnot grpmax-eligible	0.226%	442
European (non-Finnish)	0.112%	892
South Asian	0.0362%	2,760
Finnishnot grpmax-eligible	0.00313%	31,987

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.Ser460Arg
Coding: c.1380T>A
MANE Select: NM_000301
dbSNP: rs116573785
Type: single nucleotide variant
Location: chr6:160731174 (GRCh38)
Gene constraint: LOEUF 0.559 · pLI 0.17 (gnomAD)
Structure: AlphaFold pLDDT 83.53 · 49 PDB
Residue 460: a β-strand

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.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-ser460arg (accessed [today's date]).

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