Is LRP2 p.Ile397Val (c.1189A>G) pathogenic?

LRP2 p.Ile397Val (c.1189A>G) is classified Conflicting classifications of pathogenicity in LRP2 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-01-20). AlphaMissense: likely benign (0.1149); Rare (popmax 0.181%, afr).

How common is LRP2 p.Ile397Val (c.1189A>G) in the general population?

LRP2 p.Ile397Val (c.1189A>G) is rare (popmax 0.181%, afr) (gnomAD).

What do computational predictors say about LRP2 p.Ile397Val (c.1189A>G)?

AlphaMissense predicts likely benign (score 0.1149) — an in-silico prediction, not a clinical call.

LRP2 p.Ile397Val

c.1189A>G · rs140575982 · VCV1623795

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1149 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.181%, afr)

Computational evidence

Protein change
AlphaMissense	0.1149	likely benign
REVEL	0.37	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.6	GERP -0.43, phastCons 0.98
Regional constraint	o/e 0.92	unconstrained · MANE · 156 kb · p 7.9e-06 · regional, not allelic
Overall
CADD	17.5	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 0.181% African / African-American · 136/75,040 alleles

Filtering AF 0.156% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.147%

Overall 0.00911% 147/1,614,118 alleles · rare exomes 73/1,461,836 · genomes 74/152,282 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.181%	552
Admixed American	0.00833%	12,003
Remaining individualsnot grpmax-eligible	0.0048%	20,837
European (non-Finnish)	0.000254%	393,342

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.Ile397Val
Coding: c.1189A>G
MANE Select: NM_004525
dbSNP: rs140575982
Type: single nucleotide variant
Location: chr2:169280502 (GRCh38)
Gene constraint: LOEUF 0.352 · pLI 1.00 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 397: a β-strand

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

Similar variants

LRP2 p.Ile397= Likely benign ★ same residue
LRP2 c.12019+1G>A Likely pathogenic ★★ same type
LRP2 c.2639+1G>A Pathogenic/Likely pathogenic ★★ same type
LRP2 c.3667+1G>A Pathogenic/Likely pathogenic ★★ same type
LRP2 c.8452+1G>A Pathogenic ★★ same type
LRP2 p.Arg1953Ter Pathogenic/Likely pathogenic ★★ same type
LRP2 p.Arg2095Ter Pathogenic/Likely pathogenic ★★ same type
LRP2 p.Arg2225Ter Pathogenic/Likely pathogenic ★★ same type

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-ile397val (accessed [today's date]).

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