Is LRP4 p.Phe1053= (c.3159C>T) pathogenic?

LRP4 p.Phe1053= (c.3159C>T) is classified Conflicting classifications of pathogenicity in LRP4 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2026-01-27). Very rare (popmax 0.00934%, afr); Associated with sclerosteosis 2.

What condition is associated with LRP4 p.Phe1053= (c.3159C>T)?

LRP4 p.Phe1053= (c.3159C>T) is associated with sclerosteosis 2, Cenani-Lenz syndactyly syndrome, congenital myasthenic syndrome 17 (ClinVar).

How common is LRP4 p.Phe1053= (c.3159C>T) in the general population?

LRP4 p.Phe1053= (c.3159C>T) is very rare (popmax 0.00934%, afr) (gnomAD).

LRP4 p.Phe1053=

c.3159C>T · VCV3599676

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00934%, afr)

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 5	GERP -1.2, phastCons 1
Overall
CADD	19.82	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00934% African / African-American · 7/74,916 alleles

Filtering AF 0.00437% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00309%

Overall 0.00118% 19/1,613,984 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00934%	10,702
South Asian	0.00659%	15,180
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,604
Admixed American	0.00333%	29,990
European (non-Finnish)	0.000254%	393,335

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.Phe1053=
Coding: c.3159C>T
MANE Select: NM_002334
Type: single nucleotide variant
Location: chr11:46877317 (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-phe1053 (accessed [today's date]).

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