Is PLG p.Ser688Phe (c.2063C>T) pathogenic?

PLG p.Ser688Phe (c.2063C>T) is classified Uncertain significance in PLG (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-15). AlphaMissense: likely benign (0.1375); Absent from gnomAD v4.1; Associated with angioedema, hereditary, 4.

What condition is associated with PLG p.Ser688Phe (c.2063C>T)?

PLG p.Ser688Phe (c.2063C>T) is associated with angioedema, hereditary, 4, hypoplasminogenemia (ClinVar).

How common is PLG p.Ser688Phe (c.2063C>T) in the general population?

PLG p.Ser688Phe (c.2063C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PLG p.Ser688Phe (c.2063C>T)?

AlphaMissense predicts likely benign (score 0.1375) — an in-silico prediction, not a clinical call.

PLG p.Ser688Phe

c.2063C>T · VCV3593354

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1375 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

angioedema, hereditary, 4

Computational evidence

Protein change
AlphaMissense	0.1375	likely benign
REVEL	0.32	indeterminate
SaProt	LLR -9.88	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 3.3	GERP 1.7, phastCons 0.16
Regional constraint	o/e 0.92	unconstrained · MANE · 50 kb · p 0.011 · regional, not allelic
Overall
CADD	23.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: PLG
Protein: p.Ser688Phe
Coding: c.2063C>T
MANE Select: NM_000301
Type: single nucleotide variant
Location: chr6:160741355 (GRCh38)
Gene constraint: LOEUF 0.559 · pLI 0.17 (gnomAD)
Structure: AlphaFold pLDDT 83.53 · 49 PDB
Residue 688: the peptidase s1 domain; an α-helix; a modified residue (phosphoserine)

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.Ser688Cys Uncertain significance ★ same residue
PLG p.Ser688Thr 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

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-ser688phe (accessed [today's date]).

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