Is PLG p.Arg580Ser (c.1740G>T) pathogenic?

PLG p.Arg580Ser (c.1740G>T) is classified Uncertain significance in PLG (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-28). AlphaMissense: likely pathogenic (0.8017); Absent from gnomAD v4.1.

How common is PLG p.Arg580Ser (c.1740G>T) in the general population?

PLG p.Arg580Ser (c.1740G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PLG p.Arg580Ser (c.1740G>T)?

AlphaMissense predicts likely pathogenic (score 0.8017) — an in-silico prediction, not a clinical call.

PLG p.Arg580Ser

c.1740G>T · VCV4780000

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8017 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.8017	likely pathogenic
REVEL	0.5	indeterminate
SaProt	LLR -11.32	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.8	GERP -1.9, phastCons 0.97
Regional constraint	o/e 0.92	unconstrained · MANE · 50 kb · p 0.011 · regional, not allelic
Overall
CADD	19.93	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

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.Arg580Ser
Coding: c.1740G>T
MANE Select: NM_000301
Type: single nucleotide variant
Location: chr6:160736945 (GRCh38)
Gene constraint: LOEUF 0.559 · pLI 0.17 (gnomAD)
Structure: AlphaFold pLDDT 83.53 · 49 PDB
Residue 580: a functional site (cleavage; by plasminogen activators plau and plat)

Full PLG gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PLG p.Lys330Glu Pathogenic ★★ ⚠ same type
PLG p.Lys38Glu Pathogenic/Likely pathogenic ★★ ⚠ same type
PLG c.2271+5G>A Uncertain significance ★★ same type
PLG c.669-3C>G Uncertain significance ★★ same type
PLG p.Ala216Thr Uncertain significance ★★ ⚠ same type
PLG p.Ala459Val Uncertain significance ★★ ⚠ same type
PLG p.Ala494Glu Uncertain significance ★★ ⚠ same type
PLG p.Ala507Val Uncertain significance ★★ ⚠ same type

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-arg580ser (accessed [today's date]).

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