Is PLOD3 p.Pro562Ser (c.1684C>T) pathogenic?

PLOD3 p.Pro562Ser (c.1684C>T) is classified Uncertain significance in PLOD3 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-05-03). AlphaMissense: likely pathogenic (0.9106); Very rare (popmax 0.00133%, afr); Associated with bone fragility with contractures, arterial rupture, and deafness.

What condition is associated with PLOD3 p.Pro562Ser (c.1684C>T)?

PLOD3 p.Pro562Ser (c.1684C>T) is associated with bone fragility with contractures, arterial rupture, and deafness (ClinVar).

How common is PLOD3 p.Pro562Ser (c.1684C>T) in the general population?

PLOD3 p.Pro562Ser (c.1684C>T) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about PLOD3 p.Pro562Ser (c.1684C>T)?

AlphaMissense predicts likely pathogenic (score 0.9106) — an in-silico prediction, not a clinical call.

PLOD3 p.Pro562Ser

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.1684C>T · rs369002471 · VCV915354

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9106 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

bone fragility with contractures, arterial rupture, and deafness

Computational evidence

Protein change
AlphaMissense	0.9106	likely pathogenic
REVEL	0.788	moderately pathogenic-leaning
SaProt	LLR -13.26	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.31 · evaluated, not missing
Constraint at this position
Conservation	phyloP 12	GERP 4.3, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 1,452 bp · p 0.64 · regional, not allelic
Overall
CADD	34.0	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.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/74,942 alleles

Overall 0.000137% 2/1,455,428 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	74,942
South Asian	0.0011%	90,964

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.Pro562Ser
Coding: c.1684C>T
MANE Select: NM_001084
dbSNP: rs369002471
Type: single nucleotide variant
Location: chr7:101208957 (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 562: a β-strand; 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.Pro562= 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
PLOD3 p.Pro296Arg Uncertain significance ★★ ⚠ same condition
PLOD3 c.1233-4G>A Benign ★★ 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-pro562ser (accessed [today's date]).

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