Is PLOD2 p.Val523fs (c.1559dup) pathogenic?

PLOD2 p.Val523fs (c.1559dup) is classified Pathogenic in PLOD2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-28). Very rare (popmax 0.0054%, afr); Associated with osteogenesis imperfecta.

What condition is associated with PLOD2 p.Val523fs (c.1559dup)?

PLOD2 p.Val523fs (c.1559dup) is associated with osteogenesis imperfecta, Bruck syndrome 2 (ClinVar).

How common is PLOD2 p.Val523fs (c.1559dup) in the general population?

PLOD2 p.Val523fs (c.1559dup) is very rare (popmax 0.0054%, afr) (gnomAD).

How is Osteogenesis imperfecta inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

PLOD2 p.Val523fs

c.1559dup · rs749709000 · VCV41424

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.0054%, afr)

Conditions

osteogenesis imperfecta

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 14 of 20
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 4.2	GERP 1, phastCons 1
Overall
CADD	35.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0054% African / African-American · 4/74,024 alleles

Filtering AF 0.00176% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00105%

Overall 0.000572% 9/1,573,652 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0054%	18,506
East Asian	0.00225%	44,474
European (non-Finnish)	0.000349%	286,502

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.Val523fs
Coding: c.1559dup
MANE Select: NM_182943
dbSNP: rs749709000
Type: Duplication
Location: chr3:146077865 (GRCh38)
Gene constraint: LOEUF 1.209 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 92.63
Residue 523: a UniProt-annotated variant site (in brks2; likely pathogenic)

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

Disease context

osteogenesis imperfecta — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Bruck syndrome 2

For Osteogenesis imperfecta (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, X-linked recessive
Onset: All ages
Prevalence: 1-5 / 10 000 (Worldwide)

Similar variants

PLOD2 p.Cys4fs Pathogenic/Likely pathogenic ★★ same condition
PLOD2 c.339-22dup Benign ★★ same condition
PLOD2 p.Gly301fs Likely pathogenic ★ same condition
PLOD2 p.Gly534fs Likely pathogenic ★ same condition
PLOD2 p.Phe118fs Likely pathogenic ★ same condition
PLOD2 p.Val523Ile Uncertain significance ★ ⚠ same residue
PLOD2 p.Arg440Ter Pathogenic/Likely pathogenic ★★ same condition
PLOD2 p.Arg495Ter Pathogenic/Likely pathogenic ★★ 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/plod2-p-val523fs (accessed [today's date]).

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