Is LRP4 p.Arg1273= (c.3817C>A) pathogenic?

LRP4 p.Arg1273= (c.3817C>A) is classified Conflicting classifications of pathogenicity in LRP4 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-01-31). Rare (popmax 0.495%, mid); Associated with Cenani-Lenz syndactyly syndrome.

What condition is associated with LRP4 p.Arg1273= (c.3817C>A)?

LRP4 p.Arg1273= (c.3817C>A) is associated with Cenani-Lenz syndactyly syndrome, sclerosteosis 2, congenital myasthenic syndrome 17 (ClinVar).

How common is LRP4 p.Arg1273= (c.3817C>A) in the general population?

LRP4 p.Arg1273= (c.3817C>A) is rare (popmax 0.495%, mid) (gnomAD).

LRP4 p.Arg1273=

c.3817C>A · rs61746928 · VCV211405

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

rare (popmax 0.495%, mid)

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 8.7	GERP -1.4, phastCons 1
Overall
CADD	7.968	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.495% Middle Eastern · 30/6,060 alleles

Filtering AF 0.356% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.309%

Overall 0.297% 4,799/1,614,078 alleles · rare exomes 4,251/1,461,872 · genomes 548/152,206 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	1.35%	74
Middle Easterngrpmax	0.495%	202
European (non-Finnish)	0.304%	329
Remaining individualsnot grpmax-eligible	0.286%	349
Admixed American	0.085%	1,177
South Asian	0.0604%	1,656
Ashkenazi Jewishnot grpmax-eligible	0.0473%	2,115
African / African-American	0.024%	4,168

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg1273=
Coding: c.3817C>A
MANE Select: NM_002334
dbSNP: rs61746928
Type: single nucleotide variant
Location: chr11:46875564 (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

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 p.Arg1273Pro Uncertain significance ★ ⚠ same residue
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

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-arg1273 (accessed [today's date]).

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