Is PLG p.Pro647= (c.1941G>A) pathogenic?

PLG p.Pro647= (c.1941G>A) is classified Likely benign in PLG (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-22). Very rare (popmax 0.00966%, nfe).

How common is PLG p.Pro647= (c.1941G>A) in the general population?

PLG p.Pro647= (c.1941G>A) is very rare (popmax 0.00966%, nfe) (gnomAD).

PLG p.Pro647=

c.1941G>A · rs61731712 · VCV2418499

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00966%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -10	GERP -3.2
Overall
CADD	0.022	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00966% European (non-Finnish) · 114/1,180,006 alleles

Filtering AF 0.00817% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00761%

Overall 0.0115% 186/1,613,926 alleles · very rare exomes 156/1,461,838 · genomes 30/152,088 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0743%	1,346
Finnishnot grpmax-eligible	0.0469%	2,134
Remaining individualsnot grpmax-eligible	0.0144%	6,942
European (non-Finnish)grpmax	0.00966%	10,351
African / African-American	0.00801%	12,479
Admixed American	0.00667%	14,998
South Asian	0.0011%	91,062

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro647=
Coding: c.1941G>A
MANE Select: NM_000301
dbSNP: rs61731712
Type: single nucleotide variant
Location: chr6:160739131 (GRCh38)
Gene constraint: LOEUF 0.559 · pLI 0.17 (gnomAD)
Structure: AlphaFold pLDDT 83.53 · 49 PDB
Residue 647: the peptidase s1 domain

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

Similar variants

PLG p.Pro647Leu 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
PLG p.Ala494Glu 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-pro647 (accessed [today's date]).

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