Is PLOD2 p.Pro653Arg (c.1958C>G) pathogenic?

PLOD2 p.Pro653Arg (c.1958C>G) is classified Conflicting classifications of pathogenicity in PLOD2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-12-10). AlphaMissense: likely pathogenic (0.8436); Very rare (popmax 0.000764%, nfe); Associated with osteogenesis imperfecta.

What condition is associated with PLOD2 p.Pro653Arg (c.1958C>G)?

PLOD2 p.Pro653Arg (c.1958C>G) is associated with osteogenesis imperfecta, Bruck syndrome 2 (ClinVar).

How common is PLOD2 p.Pro653Arg (c.1958C>G) in the general population?

PLOD2 p.Pro653Arg (c.1958C>G) is very rare (popmax 0.000764%, nfe) (gnomAD).

How is Osteogenesis imperfecta inherited?

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

What do computational predictors say about PLOD2 p.Pro653Arg (c.1958C>G)?

AlphaMissense predicts likely pathogenic (score 0.8436) — an in-silico prediction, not a clinical call.

PLOD2 p.Pro653Arg

c.1958C>G · rs967744523 · VCV1705607

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.8436 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000764%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

osteogenesis imperfecta

Computational evidence

Protein change
AlphaMissense	0.8436	likely pathogenic
REVEL	0.833	moderately pathogenic-leaning
SaProt	LLR -13.89	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.1, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 90 kb · p 0.85 · regional, not allelic
Overall
CADD	29.8	PHRED · no single calibrated threshold — expert panels disagree

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P632R vs ClinVar P653R) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000764% European (non-Finnish) · 9/1,178,760 alleles

Filtering AF 0.000359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00026%

Overall 0.000558% 9/1,612,046 alleles · very rare

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.Pro653Arg
Coding: c.1958C>G
MANE Select: NM_182943
dbSNP: rs967744523
Type: single nucleotide variant
Location: chr3:146071314 (GRCh38)
Gene constraint: LOEUF 1.209 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 92.63
Residue 653: the fe2og dioxygenase domain; 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.Arg440Ter Pathogenic/Likely pathogenic ★★ same condition
PLOD2 p.Arg495Ter Pathogenic/Likely pathogenic ★★ same condition
PLOD2 p.Arg680Ter Pathogenic/Likely pathogenic ★★ same condition
PLOD2 c.-170C>G Uncertain significance ★★ same condition
PLOD2 p.Ala415Val Uncertain significance ★★ ⚠ same condition
PLOD2 p.Arg484Cys Uncertain significance ★★ ⚠ same condition
PLOD2 p.Arg619Cys Uncertain significance ★★ ⚠ same condition
PLOD2 p.Arg648Trp 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/plod2-p-pro653arg (accessed [today's date]).

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