Is LRP2 p.Ser123Arg (c.369T>G) pathogenic?

LRP2 p.Ser123Arg (c.369T>G) is classified Uncertain significance in LRP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-05). AlphaMissense: likely benign (0.0891); Very rare (popmax 0.00878%, sas); Associated with Inborn genetic diseases.

What condition is associated with LRP2 p.Ser123Arg (c.369T>G)?

LRP2 p.Ser123Arg (c.369T>G) is associated with Inborn genetic diseases (ClinVar).

How common is LRP2 p.Ser123Arg (c.369T>G) in the general population?

LRP2 p.Ser123Arg (c.369T>G) is very rare (popmax 0.00878%, sas) (gnomAD).

What do computational predictors say about LRP2 p.Ser123Arg (c.369T>G)?

AlphaMissense predicts likely benign (score 0.0891) — an in-silico prediction, not a clinical call.

LRP2 p.Ser123Arg

c.369T>G · rs757393374 · VCV3120250

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0891 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00878%, sas)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0891	likely benign
REVEL	0.333	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -9.4	GERP -3.8
Regional constraint	o/e 0.92	unconstrained · MANE · 156 kb · p 7.9e-06 · regional, not allelic
Overall
CADD	0.01	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 0.00878% South Asian · 8/91,084 alleles

Filtering AF 0.00437% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00312%

Overall 0.00062% 10/1,613,944 alleles · very rare exomes 9/1,461,716 · genomes 1/152,228 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00878%	11,386
Remaining individualsnot grpmax-eligible	0.0032%	31,243

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.Ser123Arg
Coding: c.369T>G
MANE Select: NM_004525
dbSNP: rs757393374
Type: single nucleotide variant
Location: chr2:169307339 (GRCh38)
Gene constraint: LOEUF 0.352 · pLI 1.00 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 123: the ldl-receptor class a 3 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

Similar variants

LRP2 p.Ser123= Likely benign ★★ same residue
LRP2 p.Ser123Asn Uncertain significance ★ ⚠ same residue
LRP2 c.5227+6G>C Uncertain significance ★★ same condition
LRP2 p.Ala1007Val Uncertain significance ★★ ⚠ same condition
LRP2 p.Ala1071Val Uncertain significance ★★ same condition
LRP2 p.Ala1105Pro Uncertain significance ★★ ⚠ same condition
LRP2 p.Ala1265Val Uncertain significance ★★ ⚠ same condition
LRP2 p.Ala1493Val 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/lrp2-p-ser123arg (accessed [today's date]).

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