Is LRP5 p.Arg752Trp (c.2254C>T) pathogenic?

LRP5 p.Arg752Trp (c.2254C>T) is classified Conflicting classifications of pathogenicity in LRP5 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-09-17). AlphaMissense: likely pathogenic (0.7798); Very rare (popmax 0.0011%, sas); Associated with LRP5-related disorder.

What condition is associated with LRP5 p.Arg752Trp (c.2254C>T)?

LRP5 p.Arg752Trp (c.2254C>T) is associated with LRP5-related disorder, exudative vitreoretinopathy 4 (ClinVar).

How common is LRP5 p.Arg752Trp (c.2254C>T) in the general population?

LRP5 p.Arg752Trp (c.2254C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about LRP5 p.Arg752Trp (c.2254C>T)?

AlphaMissense predicts likely pathogenic (score 0.7798) — an in-silico prediction, not a clinical call.

LRP5 p.Arg752Trp

c.2254C>T · rs121908674 · VCV1184509

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.7798 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

LRP5-related disorder

Computational evidence

Protein change
AlphaMissense	0.7798	likely pathogenic
REVEL	0.966	strongly pathogenic-leaning
SaProt	LLR -15.55	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.7	GERP 0.81, phastCons 1
Regional constraint	o/e 0.70	unconstrained · MANE · 99 kb · p 4.9e-23 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,086 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000479% 7/1,461,734 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,086
European (non-Finnish)	0.000508%	196,669

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: LRP5
Protein: p.Arg752Trp
Coding: c.2254C>T
MANE Select: NM_002335
dbSNP: rs121908674
Type: single nucleotide variant
Location: chr11:68410076 (GRCh38)
Gene constraint: LOEUF 0.482 · pLI 0.94 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 78.65
Residue 752: a UniProt-annotated variant site (in evr4; autosomal recessive); the 'beta-propeller 3' region

Full LRP5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

LRP5-related disorder

Also linked: exudative vitreoretinopathy 4

Similar variants

LRP5 p.Arg752Gln Likely pathogenic ★ same residue
LRP5 p.Arg752Gly Pathogenic ★ same residue
LRP5 c.3236+2T>G Pathogenic/Likely pathogenic ★★ same condition
LRP5 c.4488+2T>G Pathogenic/Likely pathogenic ★★ same condition
LRP5 p.Ala242Thr Pathogenic/Likely pathogenic ★★ same condition
LRP5 p.Ala422Ser Likely pathogenic ★★ ⚠ same condition
LRP5 p.Ala422Thr Likely pathogenic ★★ same condition
LRP5 p.Arg428Ter Pathogenic ★★ 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/lrp5-p-arg752trp (accessed [today's date]).

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