Is LRP2 p.Val2196Phe (c.6586G>T) pathogenic?

LRP2 p.Val2196Phe (c.6586G>T) is classified Uncertain significance in LRP2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-05-24). AlphaMissense: ambiguous (0.4654); Ultra-rare (popmax 0.0107%, afr); Associated with Inborn genetic diseases.

What condition is associated with LRP2 p.Val2196Phe (c.6586G>T)?

LRP2 p.Val2196Phe (c.6586G>T) is associated with Inborn genetic diseases (ClinVar).

How common is LRP2 p.Val2196Phe (c.6586G>T) in the general population?

LRP2 p.Val2196Phe (c.6586G>T) is ultra-rare (popmax 0.0107%, afr) (gnomAD).

What do computational predictors say about LRP2 p.Val2196Phe (c.6586G>T)?

AlphaMissense predicts ambiguous (score 0.4654) — an in-silico prediction, not a clinical call.

LRP2 p.Val2196Phe

c.6586G>T · rs746579590 · VCV1522229

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4654 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0107%, afr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4654	ambiguous
REVEL	0.748	pathogenic-leaning
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.1	GERP -1.6, phastCons 0.52
Regional constraint	o/e 0.92	unconstrained · MANE · 156 kb · p 7.9e-06 · regional, not allelic
Overall
CADD	19.45	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 0.0107% African / African-American · 8/74,826 alleles

Filtering AF 0.00528% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00381%

Overall 0.000496% 8/1,612,182 alleles · ultra-rare exomes 3/1,459,956 · genomes 5/152,226 · joint denominator

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.Val2196Phe
Coding: c.6586G>T
MANE Select: NM_004525
dbSNP: rs746579590
Type: single nucleotide variant
Location: chr2:169207134 (GRCh38)
Gene constraint: LOEUF 0.352 · pLI 1.00 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 2196: a β-strand

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 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
LRP2 p.Ala1515Val Uncertain significance ★★ same condition
LRP2 p.Ala1582Val 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-val2196phe (accessed [today's date]).

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