Is PLG p.Pro143Ser (c.427C>T) pathogenic?

PLG p.Pro143Ser (c.427C>T) is classified Uncertain significance in PLG (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-30). AlphaMissense: likely benign (0.181); Very rare (popmax 0.00646%, nfe).

How common is PLG p.Pro143Ser (c.427C>T) in the general population?

PLG p.Pro143Ser (c.427C>T) is very rare (popmax 0.00646%, nfe) (gnomAD).

What do computational predictors say about PLG p.Pro143Ser (c.427C>T)?

AlphaMissense predicts likely benign (score 0.181) — an in-silico prediction, not a clinical call.

PLG p.Pro143Ser

c.427C>T · rs751122910 · VCV1483323

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.181 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00646%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.181	likely benign
REVEL	0.492	indeterminate
SaProt	LLR -12.63	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 0.92, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 50 kb · p 0.011 · regional, not allelic
Overall
CADD	24.8	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 0.00646% European (non-Finnish) · 76/1,177,298 alleles

Filtering AF 0.00529% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00483%

Overall 0.00497% 80/1,609,056 alleles · very rare exomes 74/1,456,898 · genomes 6/152,158 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00646%	15,491
Remaining individualsnot grpmax-eligible	0.00643%	15,551

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.Pro143Ser
Coding: c.427C>T
MANE Select: NM_000301
dbSNP: rs751122910
Type: single nucleotide variant
Location: chr6:160713005 (GRCh38)
Gene constraint: LOEUF 0.559 · pLI 0.17 (gnomAD)
Structure: AlphaFold pLDDT 83.53 · 49 PDB
Residue 143: a turn; the 'disordered' region; the kringle 1 domain

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

Similar variants

PLG p.Pro143Arg 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-pro143ser (accessed [today's date]).

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