Is LRP4 p.Ser406= (c.1218C>T) pathogenic?

LRP4 p.Ser406= (c.1218C>T) is classified Likely benign in LRP4 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-05-13). Very rare (popmax 8.47e-05%, nfe); Associated with Cenani-Lenz syndactyly syndrome.

What condition is associated with LRP4 p.Ser406= (c.1218C>T)?

LRP4 p.Ser406= (c.1218C>T) is associated with Cenani-Lenz syndactyly syndrome, sclerosteosis 2, congenital myasthenic syndrome 17 (ClinVar).

How common is LRP4 p.Ser406= (c.1218C>T) in the general population?

LRP4 p.Ser406= (c.1218C>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

LRP4 p.Ser406=

c.1218C>T · rs2134851406 · VCV1544067

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, 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 5.8	GERP -0.12, phastCons 1
Overall
CADD	10.91	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,022 alleles

Overall 6.84e-05% 1/1,461,574 alleles · very 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: LRP4
Protein: p.Ser406=
Coding: c.1218C>T
MANE Select: NM_002334
dbSNP: rs2134851406
Type: single nucleotide variant
Location: chr11:46895257 (GRCh38)
Gene constraint: LOEUF 0.501 · pLI 0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.57 · 1 PDB
Residue 406: the egf-like 2; calcium-binding 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-ser406 (accessed [today's date]).

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