Is LOX p.Arg68Pro (c.203G>C) pathogenic?

LOX p.Arg68Pro (c.203G>C) is classified Uncertain significance in LOX (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-07-16). AlphaMissense: likely benign (0.1507); Very rare (popmax 0.00425%, nfe); Associated with aortic aneurysm, familial thoracic 10.

What condition is associated with LOX p.Arg68Pro (c.203G>C)?

LOX p.Arg68Pro (c.203G>C) is associated with aortic aneurysm, familial thoracic 10 (ClinVar).

How common is LOX p.Arg68Pro (c.203G>C) in the general population?

LOX p.Arg68Pro (c.203G>C) is very rare (popmax 0.00425%, nfe) (gnomAD).

What do computational predictors say about LOX p.Arg68Pro (c.203G>C)?

AlphaMissense predicts likely benign (score 0.1507) — an in-silico prediction, not a clinical call.

LOX p.Arg68Pro

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.203G>C · rs994242735 · VCV1330430

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1507 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00425%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

aortic aneurysm, familial thoracic 10

Computational evidence

Protein change
AlphaMissense	0.1507	likely benign
REVEL	0.111	moderately benign-leaning
SaProt	LLR -5.83	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.2	GERP 1.8, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 2,475 bp · p 0.092 · regional, not allelic
Overall
CADD	26.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00425% European (non-Finnish) · 49/1,151,648 alleles

Filtering AF 0.00326% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00293%

Overall 0.00323% 50/1,548,718 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00425%	23,503
Remaining individualsnot grpmax-eligible	0.00166%	60,212

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: LOX
Protein: p.Arg68Pro
Coding: c.203G>C
MANE Select: NM_002317
dbSNP: rs994242735
Type: single nucleotide variant
Location: chr5:122077783 (GRCh38)
Gene constraint: LOEUF 0.503 · pLI 0.98 (gnomAD)
Structure: AlphaFold pLDDT 68.06
Residue 68: the 'disordered' region

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

Disease context

aortic aneurysm, familial thoracic 10 — 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

LOX p.Arg68= Benign/Likely benign ★★ same residue
LOX p.Arg68Leu Uncertain significance ★ ⚠ same residue
LOX c.1035+1G>A Pathogenic/Likely pathogenic ★★ same condition
LOX p.Met298Arg Pathogenic/Likely pathogenic ★★ same condition
LOX p.Trp42Ter Pathogenic/Likely pathogenic ★★ same condition
LOX p.Tyr227Ter Pathogenic/Likely pathogenic ★★ same condition
LOX p.Arg122Cys Uncertain significance ★★ ⚠ same condition
LOX p.Arg88Ser 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/lox-p-arg68pro (accessed [today's date]).

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