Is PLG p.Pro265Ser (c.793C>T) pathogenic?

PLG p.Pro265Ser (c.793C>T) is classified Uncertain significance in PLG (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-04-07). AlphaMissense: likely benign (0.0787); Very rare (popmax 0.00223%, eas); Associated with Inborn genetic diseases.

What condition is associated with PLG p.Pro265Ser (c.793C>T)?

PLG p.Pro265Ser (c.793C>T) is associated with Inborn genetic diseases (ClinVar).

How common is PLG p.Pro265Ser (c.793C>T) in the general population?

PLG p.Pro265Ser (c.793C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about PLG p.Pro265Ser (c.793C>T)?

AlphaMissense predicts likely benign (score 0.0787) — an in-silico prediction, not a clinical call.

PLG p.Pro265Ser

c.793C>T · rs1157597692 · VCV2075188

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0787 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0787	likely benign
REVEL	0.094	moderately benign-leaning
SaProt	LLR -6.87	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.42 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.75	GERP 0.59, phastCons 0.076
Regional constraint	o/e 0.92	unconstrained · MANE · 50 kb · p 0.011 · regional, not allelic
Overall
CADD	16.89	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 0.00223% East Asian · 1/44,888 alleles

Filtering AF 0.000689% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000539%

Overall 0.00105% 17/1,613,220 alleles · very rare exomes 14/1,460,994 · genomes 3/152,226 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,888
Admixed American	0.00167%	60,004
African / African-American	0.00133%	74,912
European (non-Finnish)	0.00119%	84,233

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.Pro265Ser
Coding: c.793C>T
MANE Select: NM_000301
dbSNP: rs1157597692
Type: single nucleotide variant
Location: chr6:160718299 (GRCh38)
Gene constraint: LOEUF 0.559 · pLI 0.17 (gnomAD)
Structure: AlphaFold pLDDT 83.53 · 49 PDB
Residue 265: an α-helix

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

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PLG p.Arg253Cys Uncertain significance ★★ ⚠ same condition
PLG p.Arg343Gln Uncertain significance ★★ ⚠ same condition
PLG p.Arg656Trp Uncertain significance ★★ ⚠ same condition
PLG p.Asn690Asp Uncertain significance ★★ ⚠ same condition
PLG p.Asp177Asn Uncertain significance ★★ ⚠ same condition
PLG p.Asp430Glu Uncertain significance ★★ ⚠ same condition

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-pro265ser (accessed [today's date]).

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