Is PLG p.Arg786Ser (c.2356C>A) pathogenic?

PLG p.Arg786Ser (c.2356C>A) is classified Uncertain significance in PLG (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-24). AlphaMissense: likely benign (0.2982); Very rare (popmax 0.00134%, afr).

How common is PLG p.Arg786Ser (c.2356C>A) in the general population?

PLG p.Arg786Ser (c.2356C>A) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about PLG p.Arg786Ser (c.2356C>A)?

AlphaMissense predicts likely benign (score 0.2982) — an in-silico prediction, not a clinical call.

PLG p.Arg786Ser

c.2356C>A · VCV4695319

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2982 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.2982	likely benign
REVEL	0.441	indeterminate
SaProt	LLR -8.26	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.3	GERP 0.74, phastCons 0.001
Regional constraint	o/e 0.52	unconstrained · MANE · 810 bp · p 4.5e-05 · regional, not allelic
Overall
CADD	21.6	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

Grpmax group 0.00134% African / African-American · 1/74,746 alleles

Overall 0.000124% 2/1,610,036 alleles · very rare exomes 2/1,458,278 · genomes 0/151,758 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00134%	74,746
South Asian	0.0011%	90,922

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.Arg786Ser
Coding: c.2356C>A
MANE Select: NM_000301
Type: single nucleotide variant
Location: chr6:160752984 (GRCh38)
Gene constraint: LOEUF 0.559 · pLI 0.17 (gnomAD)
Structure: AlphaFold pLDDT 83.53 · 49 PDB
Residue 786: the peptidase s1 domain

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

Similar variants

PLG p.Arg786Cys Uncertain significance ★★ ⚠ same residue
PLG p.Arg786His Uncertain significance ★ ⚠ same residue
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

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-arg786ser (accessed [today's date]).

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