Is LRP4 p.Asp704= (c.2112C>T) pathogenic?

LRP4 p.Asp704= (c.2112C>T) is classified Conflicting classifications of pathogenicity in LRP4 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-09-15). Ultra-rare (popmax 0.0132%, nfe); Associated with Cenani-Lenz syndactyly syndrome.

What condition is associated with LRP4 p.Asp704= (c.2112C>T)?

LRP4 p.Asp704= (c.2112C>T) is associated with Cenani-Lenz syndactyly syndrome, sclerosteosis 2, congenital myasthenic syndrome 17 (ClinVar).

How common is LRP4 p.Asp704= (c.2112C>T) in the general population?

LRP4 p.Asp704= (c.2112C>T) is ultra-rare (popmax 0.0132%, nfe) (gnomAD).

LRP4 p.Asp704=

c.2112C>T · rs140757594 · VCV879577

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0132%, nfe)

Conditions

Cenani-Lenz syndactyly syndrome

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 3.3	GERP 0.55, phastCons 1
Overall
CADD	9.628	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0132% European (non-Finnish) · 156/1,180,038 alleles

Filtering AF 0.0115% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0108%

Overall 0.0104% 168/1,613,890 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0132%	7,564
Remaining individualsnot grpmax-eligible	0.0096%	10,414
African / African-American	0.00534%	18,731
Admixed American	0.00167%	60,004
Finnishnot grpmax-eligible	0.00157%	63,862

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.Asp704=
Coding: c.2112C>T
MANE Select: NM_002334
dbSNP: rs140757594
Type: single nucleotide variant
Location: chr11:46889514 (GRCh38)
Gene constraint: LOEUF 0.501 · pLI 0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.57 · 1 PDB
Residue 704: the egf-like 3 domain; a disulfide bond

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

Disease context

Cenani-Lenz syndactyly syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: sclerosteosis 2 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-asp704 (accessed [today's date]).

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