Is PLOD2 p.Ser528Pro (c.1582T>C) pathogenic?

PLOD2 p.Ser528Pro (c.1582T>C) is classified Uncertain significance in PLOD2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-10-23). AlphaMissense: likely pathogenic (0.9656); Very rare (popmax 0.0017%, nfe).

How common is PLOD2 p.Ser528Pro (c.1582T>C) in the general population?

PLOD2 p.Ser528Pro (c.1582T>C) is very rare (popmax 0.0017%, nfe) (gnomAD).

What do computational predictors say about PLOD2 p.Ser528Pro (c.1582T>C)?

AlphaMissense predicts likely pathogenic (score 0.9656) — an in-silico prediction, not a clinical call.

PLOD2 p.Ser528Pro

c.1582T>C · rs1936362271 · VCV2419642

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9656 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0017%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9656	likely pathogenic
REVEL	0.653	pathogenic-leaning
SaProt	LLR -15.78	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	Δ0.23	acceptor gain, 18 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 9.1	GERP -0.94, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 90 kb · p 0.85 · regional, not allelic
Overall
CADD	25.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM S507P vs ClinVar S528P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0017% European (non-Finnish) · 19/1,116,386 alleles

Filtering AF 0.00109% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000877%

Overall 0.00123% 19/1,542,956 alleles · very rare exomes 19/1,391,034 · genomes 0/151,922 · 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: PLOD2
Protein: p.Ser528Pro
Coding: c.1582T>C
MANE Select: NM_182943
dbSNP: rs1936362271
Type: single nucleotide variant
Location: chr3:146076877 (GRCh38)
Gene constraint: LOEUF 1.209 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 92.63
Residue 507 UniProt numbering: a UniProt-annotated variant site (in brks2; likely pathogenic)

Full PLOD2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PLOD2 c.1500+1G>T Pathogenic/Likely pathogenic ★★ same type
PLOD2 p.Arg440Ter Pathogenic/Likely pathogenic ★★ same type
PLOD2 p.Arg473Ter Pathogenic ★★ same type
PLOD2 p.Arg495Ter Pathogenic/Likely pathogenic ★★ same type
PLOD2 p.Arg680Ter Pathogenic/Likely pathogenic ★★ same type
PLOD2 c.1232+5T>A Uncertain significance ★★ same type
PLOD2 c.-170C>G Uncertain significance ★★ same type
PLOD2 p.Ala415Val 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/plod2-p-ser528pro (accessed [today's date]).

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