Is LRP2 p.Ala2016= (c.6048C>T) pathogenic?

LRP2 p.Ala2016= (c.6048C>T) is classified Benign/Likely benign in LRP2 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-02-01). Low-frequency (popmax 1.49%, sas); Associated with Donnai-Barrow syndrome.

What condition is associated with LRP2 p.Ala2016= (c.6048C>T)?

LRP2 p.Ala2016= (c.6048C>T) is associated with Donnai-Barrow syndrome (ClinVar).

How common is LRP2 p.Ala2016= (c.6048C>T) in the general population?

LRP2 p.Ala2016= (c.6048C>T) is low-frequency (popmax 1.49%, sas) (gnomAD).

LRP2 p.Ala2016=

c.6048C>T · rs144449508 · VCV332152

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

low-frequency (popmax 1.49%, sas)

Conditions

Donnai-Barrow syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -11	GERP -3.5
Overall
CADD	0.32	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.49% South Asian · 1,359/91,070 alleles

Filtering AF 1.43% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.4%

Overall 0.129% 2,077/1,613,904 alleles · low-frequency exomes 1,950/1,461,688 · genomes 127/152,216 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	1.49%	67
Middle Eastern	0.644%	155
Ashkenazi Jewishnot grpmax-eligible	0.236%	423
Remaining individualsnot grpmax-eligible	0.165%	607
Admixed American	0.0834%	1,200
European (non-Finnish)	0.0366%	2,731
East Asian	0.0223%	4,489
African / African-American	0.0173%	5,768
Finnishnot grpmax-eligible	0.00156%	64,016

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.Ala2016=
Coding: c.6048C>T
MANE Select: NM_004525
dbSNP: rs144449508
Type: single nucleotide variant
Location: chr2:169212200 (GRCh38)
Gene constraint: LOEUF 0.352 · pLI 1.00 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)

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 p.Ala2016Thr Uncertain significance ★★ ⚠ 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-ala2016 (accessed [today's date]).

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