Is LOX p.Ser178Pro (c.532T>C) pathogenic?

LOX p.Ser178Pro (c.532T>C) is classified Conflicting classifications of pathogenicity in LOX (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-08-22). AlphaMissense: ambiguous (0.3423); Ultra-rare (popmax 0.0176%, sas); Associated with Cardiovascular phenotype.

What condition is associated with LOX p.Ser178Pro (c.532T>C)?

LOX p.Ser178Pro (c.532T>C) is associated with Cardiovascular phenotype (ClinVar).

How common is LOX p.Ser178Pro (c.532T>C) in the general population?

LOX p.Ser178Pro (c.532T>C) is ultra-rare (popmax 0.0176%, sas) (gnomAD).

What do computational predictors say about LOX p.Ser178Pro (c.532T>C)?

AlphaMissense predicts ambiguous (score 0.3423) — an in-silico prediction, not a clinical call.

LOX p.Ser178Pro

c.532T>C · VCV3539005

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3423 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0176%, sas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.3423	ambiguous
REVEL	0.163	moderately benign-leaning
SaProt	LLR -5.39	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.13	GERP -3.6, phastCons 0.41
Regional constraint	o/e 1.09	unconstrained · MANE · 2,475 bp · p 0.092 · regional, not allelic
Overall
CADD	14.85	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 0.0176% South Asian · 16/91,092 alleles

Filtering AF 0.011% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00898%

Overall 0.00109% 16/1,461,768 alleles · ultra-rare

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.Ser178Pro
Coding: c.532T>C
MANE Select: NM_002317
Type: single nucleotide variant
Location: chr5:122077454 (GRCh38)
Gene constraint: LOEUF 0.503 · pLI 0.98 (gnomAD)
Structure: AlphaFold pLDDT 68.06

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

Similar variants

LOX p.Ser178= Benign/Likely benign ★★ same residue
LOX p.Ser178Cys Uncertain significance ★ ⚠ same residue
LOX p.Arg281Ter Pathogenic/Likely pathogenic ★★ same condition
LOX p.Gly202Ter Pathogenic/Likely pathogenic ★★ same condition
LOX c.1247+1G>A Uncertain significance ★★ same condition
LOX p.Ala100Thr Uncertain significance ★★ ⚠ same condition
LOX p.Ala107Thr Uncertain significance ★★ ⚠ same condition
LOX p.Ala147Thr 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-ser178pro (accessed [today's date]).

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