Is PLG p.Ser129Pro (c.385T>C) pathogenic?

PLG p.Ser129Pro (c.385T>C) is classified Uncertain significance in PLG (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-08). AlphaMissense: likely pathogenic (0.7681); Very rare (popmax 0.00017%, nfe); Associated with angioedema, hereditary, 4.

What condition is associated with PLG p.Ser129Pro (c.385T>C)?

PLG p.Ser129Pro (c.385T>C) is associated with angioedema, hereditary, 4, hypoplasminogenemia (ClinVar).

How common is PLG p.Ser129Pro (c.385T>C) in the general population?

PLG p.Ser129Pro (c.385T>C) is very rare (popmax 0.00017%, nfe) (gnomAD).

What do computational predictors say about PLG p.Ser129Pro (c.385T>C)?

AlphaMissense predicts likely pathogenic (score 0.7681) — an in-silico prediction, not a clinical call.

PLG p.Ser129Pro

c.385T>C · VCV3593300

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7681 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

angioedema, hereditary, 4

Computational evidence

Protein change
AlphaMissense	0.7681	likely pathogenic
REVEL	0.297	indeterminate
SaProt	LLR -13.90	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.7	GERP -2.6, phastCons 0.18
Regional constraint	o/e 0.92	unconstrained · MANE · 50 kb · p 0.011 · regional, not allelic
Overall
CADD	18.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00017% European (non-Finnish) · 2/1,179,252 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,613,262 alleles · very rare exomes 2/1,460,952 · genomes 0/152,310 · joint denominator

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.Ser129Pro
Coding: c.385T>C
MANE Select: NM_000301
Type: single nucleotide variant
Location: chr6:160711169 (GRCh38)
Gene constraint: LOEUF 0.559 · pLI 0.17 (gnomAD)
Structure: AlphaFold pLDDT 83.53 · 49 PDB
Residue 129: the 'disordered' region; the kringle 1 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.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-ser129pro (accessed [today's date]).

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