Is LRP2 p.Arg2012Lys (c.6035G>A) pathogenic?

LRP2 p.Arg2012Lys (c.6035G>A) is classified Benign in LRP2 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.0976); Common (popmax 7.8%, amr) — too common for a highly-penetrant pathogenic allele; Associated with Donnai-Barrow syndrome.

What condition is associated with LRP2 p.Arg2012Lys (c.6035G>A)?

LRP2 p.Arg2012Lys (c.6035G>A) is associated with Donnai-Barrow syndrome (ClinVar).

What do computational predictors say about LRP2 p.Arg2012Lys (c.6035G>A)?

AlphaMissense predicts likely benign (score 0.0976) — an in-silico prediction, not a clinical call.

LRP2 p.Arg2012Lys

Q: How common is LRP2 p.Arg2012Lys (c.6035G>A) in the general population?

LRP2 p.Arg2012Lys (c.6035G>A) is common (popmax 7.8%, amr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.6035G>A · rs4667596 · VCV259419

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.0976 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 7.8%, amr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Donnai-Barrow syndrome

Computational evidence

Protein change
AlphaMissense	0.0976	likely benign
REVEL	0.225	benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.24	GERP -1.6, phastCons 0.79
Regional constraint	o/e 0.92	unconstrained · MANE · 156 kb · p 7.9e-06 · regional, not allelic
Overall
CADD	14.88	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 7.8% Admixed American · 4,679/59,994 alleles

Filtering AF 7.61% ClinGen BA1/BS1 input FAF95, joint · FAF99 7.54%

Overall 2.11% 34,030/1,611,600 alleles · common exomes 31,238/1,459,340 · genomes 2,792/152,260 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	7.8%	13
East Asian	7.56%	13
Amishnot grpmax-eligible	3.18%	31
Remaining individualsnot grpmax-eligible	2.17%	46
European (non-Finnish)	1.89%	53
South Asian	1.28%	78
Middle Eastern	0.931%	107
Finnishnot grpmax-eligible	0.868%	115
Ashkenazi Jewishnot grpmax-eligible	0.717%	140
African / African-American	0.394%	254

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.Arg2012Lys
Coding: c.6035G>A
MANE Select: NM_004525
dbSNP: rs4667596
Type: single nucleotide variant
Location: chr2:169213662 (GRCh38)
Gene constraint: LOEUF 0.352 · pLI 1.00 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 2012: a UniProt-annotated variant site (in); an α-helix

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

Disease context

Donnai-Barrow syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

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
LRP2 p.Arg3184Ter 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-arg2012lys (accessed [today's date]).

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