Is LRP4 p.Ser665= (c.1995C>T) pathogenic?

LRP4 p.Ser665= (c.1995C>T) is classified Likely benign in LRP4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-08). Ultra-rare (popmax 0.0164%, mid); Associated with sclerosteosis 2.

What condition is associated with LRP4 p.Ser665= (c.1995C>T)?

LRP4 p.Ser665= (c.1995C>T) is associated with sclerosteosis 2, Cenani-Lenz syndactyly syndrome, congenital myasthenic syndrome 17 (ClinVar).

How common is LRP4 p.Ser665= (c.1995C>T) in the general population?

LRP4 p.Ser665= (c.1995C>T) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

LRP4 p.Ser665=

c.1995C>T · rs777406506 · VCV2047370

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

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 -0.13	GERP -3.7, phastCons 0.005
Overall
CADD	5.865	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.00111% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0009%

Overall 0.00149% 24/1,613,976 alleles · ultra-rare exomes 23/1,461,852 · genomes 1/152,124 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
African / African-American	0.00267%	37,450
European (non-Finnish)	0.00169%	59,001
South Asian	0.0011%	91,066

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.Ser665=
Coding: c.1995C>T
MANE Select: NM_002334
dbSNP: rs777406506
Type: single nucleotide variant
Location: chr11:46890041 (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 p.Ser665Gly 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-ser665 (accessed [today's date]).

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