Is PLG p.Pro135Ser (c.403C>T) pathogenic?

PLG p.Pro135Ser (c.403C>T) is classified Uncertain significance in PLG (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-13). AlphaMissense: ambiguous (0.4059); Ultra-rare (popmax 0.0174%, afr).

How common is PLG p.Pro135Ser (c.403C>T) in the general population?

PLG p.Pro135Ser (c.403C>T) is ultra-rare (popmax 0.0174%, afr) (gnomAD).

What do computational predictors say about PLG p.Pro135Ser (c.403C>T)?

AlphaMissense predicts ambiguous (score 0.4059) — an in-silico prediction, not a clinical call.

PLG p.Pro135Ser

c.403C>T · rs199833895 · VCV3013882

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4059 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0174%, afr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4059	ambiguous
REVEL	0.268	benign-leaning
SaProt	LLR -3.87	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.9, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 50 kb · p 0.011 · regional, not allelic
Overall
CADD	23.3	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 0.0174% African / African-American · 13/74,898 alleles

Filtering AF 0.0103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00813%

Overall 0.00155% 25/1,613,220 alleles · ultra-rare exomes 9/1,461,060 · genomes 16/152,160 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0174%	5,761
Admixed American	0.015%	6,664
Remaining individualsnot grpmax-eligible	0.0016%	62,440
European (non-Finnish)	0.00017%	589,685

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.Pro135Ser
Coding: c.403C>T
MANE Select: NM_000301
dbSNP: rs199833895
Type: single nucleotide variant
Location: chr6:160711187 (GRCh38)
Gene constraint: LOEUF 0.559 · pLI 0.17 (gnomAD)
Structure: AlphaFold pLDDT 83.53 · 49 PDB
Residue 135: 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.Pro135= Likely benign ★ 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-pro135ser (accessed [today's date]).

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