Is LOX p.Ser280Arg (c.840C>A) pathogenic?

LOX p.Ser280Arg (c.840C>A) is classified Conflicting classifications of pathogenicity in LOX (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-12-23). AlphaMissense: likely pathogenic (0.9288); Very rare (popmax 0.00334%, amr); Associated with Cardiovascular phenotype.

What condition is associated with LOX p.Ser280Arg (c.840C>A)?

LOX p.Ser280Arg (c.840C>A) is associated with Cardiovascular phenotype, aortic aneurysm, familial thoracic 10 (ClinVar).

How common is LOX p.Ser280Arg (c.840C>A) in the general population?

LOX p.Ser280Arg (c.840C>A) is very rare (popmax 0.00334%, amr) (gnomAD).

What do computational predictors say about LOX p.Ser280Arg (c.840C>A)?

AlphaMissense predicts likely pathogenic (score 0.9288) — an in-silico prediction, not a clinical call.

LOX p.Ser280Arg

c.840C>A · rs370861938 · VCV1343849

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.9288 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00334%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.9288	likely pathogenic
REVEL	0.229	benign-leaning
SaProt	LLR -10.94	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 0.74	GERP -1.8, phastCons 1
Regional constraint	o/e 0.54	unconstrained · MANE · 8,763 bp · p 6.1e-11 · regional, not allelic
Overall
CADD	21.3	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 0.00334% Admixed American · 2/59,936 alleles

Filtering AF 0.000554% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000313%

Overall 0.000744% 12/1,613,514 alleles · very rare exomes 10/1,461,356 · genomes 2/152,158 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00334%	29,968
European (non-Finnish)	0.000848%	117,977

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.Ser280Arg
Coding: c.840C>A
MANE Select: NM_002317
dbSNP: rs370861938
Type: single nucleotide variant
Location: chr5:122075442 (GRCh38)
Gene constraint: LOEUF 0.503 · pLI 0.98 (gnomAD)
Structure: AlphaFold pLDDT 68.06
Residue 280: a UniProt-annotated variant site (in aat10; 50% decrease of lysyl oxidase activity); the 'lysyl-oxidase like' region

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

Disease context

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: aortic aneurysm, familial thoracic 10

Similar variants

LOX p.Ser280= Likely benign ★★ same residue
LOX p.Ser280Ile Pathogenic ⚠ same residue
LOX c.1035+1G>A Pathogenic/Likely pathogenic ★★ same condition
LOX p.Arg281Ter Pathogenic/Likely pathogenic ★★ same condition
LOX p.Gly202Ter 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

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-ser280arg (accessed [today's date]).

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