Is LRP2 p.Ala57Ser (c.169G>T) pathogenic?

LRP2 p.Ala57Ser (c.169G>T) is classified Conflicting classifications of pathogenicity in LRP2 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-01-25). AlphaMissense: likely benign (0.058); Rare (popmax 0.129%, afr); Associated with Donnai-Barrow syndrome.

What condition is associated with LRP2 p.Ala57Ser (c.169G>T)?

LRP2 p.Ala57Ser (c.169G>T) is associated with Donnai-Barrow syndrome (ClinVar).

How common is LRP2 p.Ala57Ser (c.169G>T) in the general population?

LRP2 p.Ala57Ser (c.169G>T) is rare (popmax 0.129%, afr) (gnomAD).

What do computational predictors say about LRP2 p.Ala57Ser (c.169G>T)?

AlphaMissense predicts likely benign (score 0.058) — an in-silico prediction, not a clinical call.

LRP2 p.Ala57Ser

c.169G>T · rs147295930 · VCV1131477

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.058 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.129%, afr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Donnai-Barrow syndrome

Computational evidence

Protein change
AlphaMissense	0.058	likely benign
REVEL	0.276	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 -1.3	GERP -4.1
Regional constraint	o/e 0.92	unconstrained · MANE · 156 kb · p 7.9e-06 · regional, not allelic
Overall
CADD	0.003	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 0.129% African / African-American · 97/75,044 alleles

Filtering AF 0.108% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.101%

Overall 0.00681% 110/1,614,102 alleles · rare exomes 49/1,461,804 · genomes 61/152,298 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.129%	774
Admixed American	0.0117%	8,572
Remaining individualsnot grpmax-eligible	0.008%	12,501
South Asian	0.0011%	91,088

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.Ala57Ser
Coding: c.169G>T
MANE Select: NM_004525
dbSNP: rs147295930
Type: single nucleotide variant
Location: chr2:169320795 (GRCh38)
Gene constraint: LOEUF 0.352 · pLI 1.00 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 57: the ldl-receptor class a 1 domain

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.Ala57Gly Uncertain significance ★ same residue
LRP2 p.Ala57Val Conflicting classifications of pathogenicity ★ same residue
LRP2 p.Ala57= Likely benign ★ 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

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-ala57ser (accessed [today's date]).

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