Is PLOD3 p.Pro296Arg (c.887C>G) pathogenic?

PLOD3 p.Pro296Arg (c.887C>G) is classified Uncertain significance in PLOD3 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2022-10-18). AlphaMissense: likely benign (0.2335); Rare (popmax 0.148%, afr); Associated with bone fragility with contractures, arterial rupture, and deafness.

What condition is associated with PLOD3 p.Pro296Arg (c.887C>G)?

PLOD3 p.Pro296Arg (c.887C>G) is associated with bone fragility with contractures, arterial rupture, and deafness (ClinVar).

How common is PLOD3 p.Pro296Arg (c.887C>G) in the general population?

PLOD3 p.Pro296Arg (c.887C>G) is rare (popmax 0.148%, afr) (gnomAD).

What do computational predictors say about PLOD3 p.Pro296Arg (c.887C>G)?

AlphaMissense predicts likely benign (score 0.2335) — an in-silico prediction, not a clinical call.

PLOD3 p.Pro296Arg

Q: How is Connective tissue disorder due to lysyl hydroxylase-3 deficiency inherited?

Typically Not applicable (Orphanet). A genetic counselor can assess individual risk for a family.

c.887C>G · rs143577626 · VCV547022

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.2335 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.148%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

bone fragility with contractures, arterial rupture, and deafness

Computational evidence

Protein change
AlphaMissense	0.2335	likely benign
REVEL	0.794	moderately pathogenic-leaning
SaProt	LLR -11.75	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 4, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 6,691 bp · p 0.12 · regional, not allelic
Overall
CADD	26.7	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.148% African / African-American · 111/74,976 alleles

Filtering AF 0.126% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.117%

Overall 0.0212% 342/1,613,798 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.148%	675
Middle Eastern	0.0844%	1,184
Remaining individualsnot grpmax-eligible	0.0544%	1,838
East Asian	0.0446%	2,243
South Asian	0.0395%	2,530
Admixed American	0.0333%	3,000
European (non-Finnish)	0.00966%	10,351
Finnishnot grpmax-eligible	0.00312%	32,011

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: PLOD3
Protein: p.Pro296Arg
Coding: c.887C>G
MANE Select: NM_001084
dbSNP: rs143577626
Type: single nucleotide variant
Location: chr7:101212648 (GRCh38)
Gene constraint: LOEUF 0.925 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 91.80 · 18 PDB
Residue 296: the 'accessory region' region; an α-helix

Full PLOD3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

bone fragility with contractures, arterial rupture, and deafness — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Connective tissue disorder due to lysyl hydroxylase-3 deficiency (Orphanet):

Inheritance: Not applicable
Onset: Antenatal, Neonatal
Prevalence: <1 / 1 000 000 (Worldwide)

Similar variants

PLOD3 p.Pro296His Conflicting classifications of pathogenicity ★ ⚠ same residue
PLOD3 p.Pro296Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
PLOD3 p.Pro296= Likely benign ★ same residue
PLOD3 c.1359-1G>C Likely pathogenic ★★ same condition
PLOD3 p.Arg452Ter Pathogenic ★★ same condition
PLOD3 p.Tyr630Ter Pathogenic/Likely pathogenic ★★ same condition
PLOD3 p.Asp326Asn Uncertain significance ★★ ⚠ same condition
PLOD3 p.Gly224Arg 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/plod3-p-pro296arg (accessed [today's date]).

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