Is PLOD1 p.Arg118Pro (c.353G>C) pathogenic?

PLOD1 p.Arg118Pro (c.353G>C) is classified Uncertain significance in PLOD1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-11-22). AlphaMissense: likely pathogenic (0.7729); Very rare (popmax 0.00167%, amr); Associated with familial thoracic aortic aneurysm and aortic dissection.

What condition is associated with PLOD1 p.Arg118Pro (c.353G>C)?

PLOD1 p.Arg118Pro (c.353G>C) is associated with familial thoracic aortic aneurysm and aortic dissection (ClinVar).

How common is PLOD1 p.Arg118Pro (c.353G>C) in the general population?

PLOD1 p.Arg118Pro (c.353G>C) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about PLOD1 p.Arg118Pro (c.353G>C)?

AlphaMissense predicts likely pathogenic (score 0.7729) — an in-silico prediction, not a clinical call.

PLOD1 p.Arg118Pro

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.353G>C · VCV3420932

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7729 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

familial thoracic aortic aneurysm and aortic dissection

Computational evidence

Protein change
AlphaMissense	0.7729	likely pathogenic
REVEL	0.215	benign-leaning
SaProt	LLR -14.78	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.7	GERP -3.5, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 40 kb · p 0.03 · regional, not allelic
Overall
CADD	24.3	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 0.00167% Admixed American · 1/60,014 alleles

Overall 0.000137% 2/1,461,810 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,014
European (non-Finnish)	8.47e-05%	1,179,960

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: PLOD1
Protein: p.Arg118Pro
Coding: c.353G>C
MANE Select: NM_000302
Type: single nucleotide variant
Location: chr1:11950407 (GRCh38)
Gene constraint: LOEUF 0.938 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 93.04

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

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

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood

Similar variants

PLOD1 p.Arg118Gln Uncertain significance ★★ ⚠ same residue
PLOD1 p.Arg118= Conflicting classifications of pathogenicity ★ same residue
PLOD1 p.Arg118Trp Uncertain significance ★★ ⚠ same residue
PLOD1 c.1097+1G>A 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.467-2A>G Likely pathogenic ★★ same condition
PLOD1 p.Ala667Thr 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-arg118pro (accessed [today's date]).

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