Is LRP4 p.Pro455= (c.1365A>G) pathogenic?

LRP4 p.Pro455= (c.1365A>G) is classified Benign/Likely benign in LRP4 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-12-19). Low-frequency (popmax 1.12%, sas); Associated with sclerosteosis 2.

What condition is associated with LRP4 p.Pro455= (c.1365A>G)?

LRP4 p.Pro455= (c.1365A>G) is associated with sclerosteosis 2, Cenani-Lenz syndactyly syndrome, congenital myasthenic syndrome 17 (ClinVar).

How common is LRP4 p.Pro455= (c.1365A>G) in the general population?

LRP4 p.Pro455= (c.1365A>G) is low-frequency (popmax 1.12%, sas) (gnomAD).

LRP4 p.Pro455=

c.1365A>G · rs143481229 · VCV706476

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

low-frequency (popmax 1.12%, sas)

Conditions

sclerosteosis 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.3	GERP -1.4, phastCons 1
Overall
CADD	11.75	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.12% South Asian · 1,016/91,078 alleles

Filtering AF 1.06% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.04%

Overall 0.0671% 1,083/1,614,174 alleles · low-frequency

Ancestry group	Frequency	1 in
South Asiangrpmax	1.12%	90
Remaining individualsnot grpmax-eligible	0.0736%	1,359
Middle Eastern	0.0165%	6,062
East Asian	0.00446%	22,444
Admixed American	0.00333%	30,015
African / African-American	0.00133%	75,044
European (non-Finnish)	0.00127%	78,667

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: LRP4
Protein: p.Pro455=
Coding: c.1365A>G
MANE Select: NM_002334
dbSNP: rs143481229
Type: single nucleotide variant
Location: chr11:46894764 (GRCh38)
Gene constraint: LOEUF 0.501 · pLI 0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.57 · 1 PDB

Full LRP4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

sclerosteosis 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Cenani-Lenz syndactyly syndrome congenital myasthenic syndrome 17

Similar variants

LRP4 c.316+1G>A Pathogenic ★★ same condition
LRP4 c.547+1G>A Likely pathogenic ★★ same condition
LRP4 p.Gln944Ter Pathogenic ★★ same condition
LRP4 p.Glu1233Ala Pathogenic/Likely pathogenic ★★ ⚠ same condition
LRP4 c.1309+6G>T Uncertain significance ★★ same condition
LRP4 c.2215+5G>A Uncertain significance ★★ same condition
LRP4 c.2216-3C>T Uncertain significance ★★ same condition
LRP4 c.3277+5G>T 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/lrp4-p-pro455 (accessed [today's date]).

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