Is PLOD3 p.Asp659= (c.1977C>T) pathogenic?

PLOD3 p.Asp659= (c.1977C>T) is classified Benign in PLOD3 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-02). Common (popmax 7.85%, eas) — too common for a highly-penetrant pathogenic allele; Associated with bone fragility with contractures, arterial rupture, and deafness.

What condition is associated with PLOD3 p.Asp659= (c.1977C>T)?

PLOD3 p.Asp659= (c.1977C>T) is associated with bone fragility with contractures, arterial rupture, and deafness (ClinVar).

PLOD3 p.Asp659=

Q: How common is PLOD3 p.Asp659= (c.1977C>T) in the general population?

PLOD3 p.Asp659= (c.1977C>T) is common (popmax 7.85%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

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.1977C>T · rs11546151 · VCV440171

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Common

common (popmax 7.85%, eas) — too common for a highly-penetrant pathogenic allele

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	0.014	strongly benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -3.6	GERP -4.3
Overall
CADD	0.32	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 7.85% East Asian · 3,314/42,190 alleles

Filtering AF 7.63% ClinGen BA1/BS1 input FAF95, joint · FAF99 7.54%

Overall 1.18% 18,497/1,562,240 alleles · common exomes 16,154/1,410,028 · genomes 2,343/152,212 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	7.85%	13
African / African-American	2.47%	40
South Asian	1.83%	55
Remaining individualsnot grpmax-eligible	1.7%	59
European (non-Finnish)	0.881%	113
Admixed American	0.773%	129
Ashkenazi Jewishnot grpmax-eligible	0.487%	205
Middle Eastern	0.484%	207
Finnishnot grpmax-eligible	0.0762%	1,313

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.Asp659=
Coding: c.1977C>T
MANE Select: NM_001084
dbSNP: rs11546151
Type: single nucleotide variant
Location: chr7:101206863 (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 659: a β-strand; the fe2og dioxygenase domain; 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 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
PLOD3 p.Arg468Gly 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-asp659 (accessed [today's date]).

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