Is PLOD3 p.Pro662= (c.1986G>A) pathogenic?

PLOD3 p.Pro662= (c.1986G>A) is classified Benign in PLOD3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-02-03). Low-frequency (popmax 2.85%, eas); Associated with bone fragility with contractures, arterial rupture, and deafness.

What condition is associated with PLOD3 p.Pro662= (c.1986G>A)?

PLOD3 p.Pro662= (c.1986G>A) is associated with bone fragility with contractures, arterial rupture, and deafness (ClinVar).

How common is PLOD3 p.Pro662= (c.1986G>A) in the general population?

PLOD3 p.Pro662= (c.1986G>A) is low-frequency (popmax 2.85%, eas) (gnomAD).

PLOD3 p.Pro662=

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.1986G>A · rs117761436 · VCV717332

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

low-frequency (popmax 2.85%, eas)

Conditions

bone fragility with contractures, arterial rupture, and deafness

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.021	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.92	GERP -3.6
Overall
CADD	5.731	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 2.85% East Asian · 1,212/42,490 alleles

Filtering AF 2.72% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.67%

Overall 0.0992% 1,553/1,566,206 alleles · low-frequency

Ancestry group	Frequency	1 in
East Asiangrpmax	2.85%	35
Remaining individualsnot grpmax-eligible	0.306%	327
South Asian	0.109%	915
Admixed American	0.0382%	2,618
African / African-American	0.0175%	5,700
European (non-Finnish)	0.00251%	39,831

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.Pro662=
Coding: c.1986G>A
MANE Select: NM_001084
dbSNP: rs117761436
Type: single nucleotide variant
Location: chr7:101206854 (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 662: the fe2og dioxygenase domain; a disulfide bond; a UniProt-annotated variant site (in bcard; uncertain significance)

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.Pro662Leu Uncertain significance ★★ same residue
PLOD3 p.Pro662Gln Conflicting classifications of pathogenicity ★ 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
PLOD3 p.Pro296Arg 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-pro662 (accessed [today's date]).

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