Is PLG p.Ser355Pro (c.1063T>C) pathogenic?

PLG p.Ser355Pro (c.1063T>C) is classified Uncertain significance in PLG (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-13). AlphaMissense: likely benign (0.0685); Very rare (popmax 0.00833%, amr).

How common is PLG p.Ser355Pro (c.1063T>C) in the general population?

PLG p.Ser355Pro (c.1063T>C) is very rare (popmax 0.00833%, amr) (gnomAD).

What do computational predictors say about PLG p.Ser355Pro (c.1063T>C)?

AlphaMissense predicts likely benign (score 0.0685) — an in-silico prediction, not a clinical call.

PLG p.Ser355Pro

c.1063T>C · rs767801113 · VCV2972618

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0685 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00833%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0685	likely benign
REVEL	0.017	moderately benign-leaning
SaProt	LLR -4.43	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.21	GERP -2.4, phastCons 0.014
Regional constraint	o/e 0.92	unconstrained · MANE · 50 kb · p 0.011 · regional, not allelic
Overall
CADD	10.84	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 0.00833% Admixed American · 5/60,002 alleles

Filtering AF 0.00323% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00207%

Overall 0.00031% 5/1,613,756 alleles · very rare exomes 5/1,461,524 · genomes 0/152,232 · joint denominator

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.Ser355Pro
Coding: c.1063T>C
MANE Select: NM_000301
dbSNP: rs767801113
Type: single nucleotide variant
Location: chr6:160718805 (GRCh38)
Gene constraint: LOEUF 0.559 · pLI 0.17 (gnomAD)
Structure: AlphaFold pLDDT 83.53 · 49 PDB

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

Similar variants

PLG p.Ser355Thr 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-ser355pro (accessed [today's date]).

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