Is PLG p.Pro522Ser (c.1564C>T) pathogenic?

PLG p.Pro522Ser (c.1564C>T) is classified Uncertain significance in PLG (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-08-26). AlphaMissense: likely benign (0.1481); Very rare (popmax 0.00801%, afr); Associated with hypoplasminogenemia.

What condition is associated with PLG p.Pro522Ser (c.1564C>T)?

PLG p.Pro522Ser (c.1564C>T) is associated with hypoplasminogenemia, angioedema, hereditary, 4 (ClinVar).

How common is PLG p.Pro522Ser (c.1564C>T) in the general population?

PLG p.Pro522Ser (c.1564C>T) is very rare (popmax 0.00801%, afr) (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.Pro522Ser (c.1564C>T)?

AlphaMissense predicts likely benign (score 0.1481) — an in-silico prediction, not a clinical call.

PLG p.Pro522Ser

c.1564C>T · VCV3593339

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1481 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00801%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

hypoplasminogenemia

Computational evidence

Protein change
AlphaMissense	0.1481	likely benign
REVEL	0.362	indeterminate
SaProt	LLR -11.93	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 3.1	GERP 1.6, phastCons 0.98
Regional constraint	o/e 0.92	unconstrained · MANE · 50 kb · p 0.011 · regional, not allelic
Overall
CADD	22.9	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 0.00801% African / African-American · 6/74,904 alleles

Filtering AF 0.00347% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00229%

Overall 0.000372% 6/1,614,020 alleles · very rare exomes 0/1,461,858 · genomes 6/152,162 · 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.Pro522Ser
Coding: c.1564C>T
MANE Select: NM_000301
Type: single nucleotide variant
Location: chr6:160731870 (GRCh38)
Gene constraint: LOEUF 0.559 · pLI 0.17 (gnomAD)
Structure: AlphaFold pLDDT 83.53 · 49 PDB
Residue 522: the kringle 5 domain; a turn

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

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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-pro522ser (accessed [today's date]).

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