Is LRP5 p.Ser55Phe (c.164C>T) pathogenic?

LRP5 p.Ser55Phe (c.164C>T) is classified Uncertain significance in LRP5 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-07-31). AlphaMissense: likely pathogenic (0.9274); Ultra-rare (popmax 0.0267%, amr); Associated with exudative vitreoretinopathy 1.

What condition is associated with LRP5 p.Ser55Phe (c.164C>T)?

LRP5 p.Ser55Phe (c.164C>T) is associated with exudative vitreoretinopathy 1, osteoporosis, autosomal dominant osteosclerosis, Worth type (ClinVar).

How common is LRP5 p.Ser55Phe (c.164C>T) in the general population?

LRP5 p.Ser55Phe (c.164C>T) is ultra-rare (popmax 0.0267%, amr) (gnomAD).

What do computational predictors say about LRP5 p.Ser55Phe (c.164C>T)?

AlphaMissense predicts likely pathogenic (score 0.9274) — an in-silico prediction, not a clinical call.

LRP5 p.Ser55Phe

c.164C>T · rs148462220 · VCV1041160

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely pathogenic

0.9274 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0267%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

exudative vitreoretinopathy 1

Computational evidence

Protein change
AlphaMissense	0.9274	likely pathogenic
REVEL	0.559	indeterminate
SaProt	LLR -12.11	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 3.8, phastCons 1
Regional constraint	o/e 0.70	unconstrained · MANE · 99 kb · p 4.9e-23 · regional, not allelic
Overall
CADD	23.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0267% Admixed American · 16/60,010 alleles

Filtering AF 0.0208% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0199%

Overall 0.0183% 296/1,613,546 alleles · ultra-rare exomes 281/1,461,306 · genomes 15/152,240 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0267%	3,751
European (non-Finnish)	0.023%	4,338
Remaining individualsnot grpmax-eligible	0.0064%	15,620
African / African-American	0.00534%	18,734

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.Ser55Phe
Coding: c.164C>T
MANE Select: NM_002335
dbSNP: rs148462220
Type: single nucleotide variant
Location: chr11:68347919 (GRCh38)
Gene constraint: LOEUF 0.482 · pLI 0.94 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 78.65
Residue 55: the 'beta-propeller 1' region

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

Disease context

exudative vitreoretinopathy 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: osteoporosis autosomal dominant osteosclerosis, Worth type osteoporosis-pseudoglioma syndrome exudative vitreoretinopathy 4 autosomal dominant osteopetrosis 1 polycystic liver disease 4 with or without kidney cysts

Similar variants

LRP5 p.Ser55= Likely benign ★★ same residue
LRP5 c.1412+1G>A Pathogenic ★★ same condition
LRP5 c.3236+2T>G Pathogenic/Likely pathogenic ★★ same condition
LRP5 c.4488+2T>G Pathogenic/Likely pathogenic ★★ same condition
LRP5 p.Ala214Thr Pathogenic ★★ same condition
LRP5 p.Ala242Thr Pathogenic/Likely pathogenic ★★ same condition
LRP5 p.Ala422Thr Likely pathogenic ★★ same condition
LRP5 p.Arg1078Ter 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-ser55phe (accessed [today's date]).

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