Is PLOD1 p.Arg684Pro (c.2051G>C) pathogenic?

PLOD1 p.Arg684Pro (c.2051G>C) is classified Uncertain significance in PLOD1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-03-31). AlphaMissense: likely pathogenic (0.9909); Absent from gnomAD v4.1; Associated with familial thoracic aortic aneurysm and aortic dissection.

How common is PLOD1 p.Arg684Pro (c.2051G>C) in the general population?

PLOD1 p.Arg684Pro (c.2051G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PLOD1 p.Arg684Pro (c.2051G>C)?

AlphaMissense predicts likely pathogenic (score 0.9909) — an in-silico prediction, not a clinical call.

PLOD1 p.Arg684Pro

Q: What condition is associated with PLOD1 p.Arg684Pro (c.2051G>C)?

PLOD1 p.Arg684Pro (c.2051G>C) is associated with familial thoracic aortic aneurysm and aortic dissection, Ehlers-Danlos syndrome, kyphoscoliotic type 1 (ClinVar).

Q: How is Familial thoracic aortic aneurysm and aortic dissection inherited?

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

c.2051G>C · rs772498138 · VCV1714590

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9909 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

familial thoracic aortic aneurysm and aortic dissection

Computational evidence

Protein change
AlphaMissense	0.9909	likely pathogenic · top 4% in PLOD1
REVEL	0.823	moderately pathogenic-leaning
SaProt	LLR -14.89	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 2.6, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 40 kb · p 0.03 · regional, not allelic
Overall
CADD	33.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: PLOD1
Protein: p.Arg684Pro
Coding: c.2051G>C
MANE Select: NM_000302
dbSNP: rs772498138
Type: single nucleotide variant
Location: chr1:11974675 (GRCh38)
Gene constraint: LOEUF 0.938 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 93.04
Residue 684: the fe2og dioxygenase domain

Full PLOD1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

familial thoracic aortic aneurysm and aortic dissection — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Ehlers-Danlos syndrome, kyphoscoliotic type 1

For Familial thoracic aortic aneurysm and aortic dissection (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood

Similar variants

PLOD1 p.Arg684Cys Uncertain significance ★★ ⚠ same residue
PLOD1 p.Arg684His Uncertain significance ★★ ⚠ same residue
PLOD1 c.1097+1G>A Pathogenic/Likely pathogenic ★★ same condition
PLOD1 c.1202+2T>C Likely pathogenic ★★ same condition
PLOD1 c.1470+2T>C Pathogenic/Likely pathogenic ★★ same condition
PLOD1 c.1471-2A>G Likely pathogenic ★★ same condition
PLOD1 c.1651-2A>G Pathogenic/Likely pathogenic ★★ same condition
PLOD1 c.168+1G>T Likely pathogenic ★★ 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/plod1-p-arg684pro (accessed [today's date]).

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