Is LRP4 p.Pro183Ser (c.547C>T) pathogenic?

LRP4 p.Pro183Ser (c.547C>T) is classified Uncertain significance in LRP4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-08-23). AlphaMissense: likely benign (0.0726); Ultra-rare (popmax 0.0223%, eas); Associated with sclerosteosis 2.

What condition is associated with LRP4 p.Pro183Ser (c.547C>T)?

LRP4 p.Pro183Ser (c.547C>T) is associated with sclerosteosis 2, Cenani-Lenz syndactyly syndrome, congenital myasthenic syndrome 17 (ClinVar).

How common is LRP4 p.Pro183Ser (c.547C>T) in the general population?

LRP4 p.Pro183Ser (c.547C>T) is ultra-rare (popmax 0.0223%, eas) (gnomAD).

What do computational predictors say about LRP4 p.Pro183Ser (c.547C>T)?

AlphaMissense predicts likely benign (score 0.0726) — an in-silico prediction, not a clinical call.

LRP4 p.Pro183Ser

c.547C>T · rs765567296 · VCV1481441

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0726 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0223%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

sclerosteosis 2

Computational evidence

Protein change
AlphaMissense	0.0726	likely benign
REVEL	0.491	indeterminate
SaProt	LLR -6.03	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Overall
CADD	25.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0223% East Asian · 10/44,888 alleles

Filtering AF 0.012% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00916%

Overall 0.00199% 32/1,611,742 alleles · ultra-rare exomes 31/1,459,556 · genomes 1/152,186 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0223%	4,489
Remaining individualsnot grpmax-eligible	0.016%	6,242
European (non-Finnish)	0.00102%	98,168

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.Pro183Ser
Coding: c.547C>T
MANE Select: NM_002334
dbSNP: rs765567296
Type: single nucleotide variant
Location: chr11:46899387 (GRCh38)
Gene constraint: LOEUF 0.501 · pLI 0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.57 · 1 PDB
Residue 183: the ldl-receptor class a 4 domain

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-pro183ser (accessed [today's date]).

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