Is LRP2 p.Pro1223Ser (c.3667C>T) pathogenic?

LRP2 p.Pro1223Ser (c.3667C>T) is classified Uncertain significance in LRP2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-10-21). AlphaMissense: likely benign (0.1022); Ultra-rare (popmax 0.0508%, afr); Associated with Inborn genetic diseases.

What condition is associated with LRP2 p.Pro1223Ser (c.3667C>T)?

LRP2 p.Pro1223Ser (c.3667C>T) is associated with Inborn genetic diseases, Donnai-Barrow syndrome (ClinVar).

How common is LRP2 p.Pro1223Ser (c.3667C>T) in the general population?

LRP2 p.Pro1223Ser (c.3667C>T) is ultra-rare (popmax 0.0508%, afr) (gnomAD).

What do computational predictors say about LRP2 p.Pro1223Ser (c.3667C>T)?

AlphaMissense predicts likely benign (score 0.1022) — an in-silico prediction, not a clinical call.

LRP2 p.Pro1223Ser

c.3667C>T · rs145657082 · VCV1051876

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1022 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0508%, afr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1022	likely benign
REVEL	0.302	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.9	GERP -1, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 156 kb · p 7.9e-06 · regional, not allelic
Overall
CADD	18.62	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0508% African / African-American · 38/74,810 alleles

Filtering AF 0.038% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0335%

Overall 0.00317% 51/1,611,342 alleles · ultra-rare exomes 31/1,459,272 · genomes 20/152,070 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0508%	1,969
East Asian	0.00223%	44,868
South Asian	0.0011%	91,006
European (non-Finnish)	0.000934%	107,062

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: LRP2
Protein: p.Pro1223Ser
Coding: c.3667C>T
MANE Select: NM_004525
dbSNP: rs145657082
Type: single nucleotide variant
Location: chr2:169242956 (GRCh38)
Gene constraint: LOEUF 0.352 · pLI 1.00 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 1223: the ldl-receptor class a 12 domain

Full LRP2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Donnai-Barrow syndrome

Similar variants

LRP2 p.Pro1223= Likely benign ★ same residue
LRP2 c.12019+1G>A Likely pathogenic ★★ same condition
LRP2 c.2639+1G>A Pathogenic/Likely pathogenic ★★ same condition
LRP2 c.3667+1G>A Pathogenic/Likely pathogenic ★★ same condition
LRP2 c.8452+1G>A Pathogenic ★★ same condition
LRP2 p.Arg1953Ter Pathogenic/Likely pathogenic ★★ same condition
LRP2 p.Arg2225Ter Pathogenic/Likely pathogenic ★★ same condition
LRP2 p.Arg278Ter Pathogenic/Likely 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/lrp2-p-pro1223ser (accessed [today's date]).

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