Is LRP2 p.Pro2278Ser (c.6832C>T) pathogenic?

LRP2 p.Pro2278Ser (c.6832C>T) is classified Uncertain significance in LRP2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-03-14). AlphaMissense: likely pathogenic (0.5851); Very rare (popmax 0.0011%, sas); Associated with Donnai-Barrow syndrome.

What condition is associated with LRP2 p.Pro2278Ser (c.6832C>T)?

LRP2 p.Pro2278Ser (c.6832C>T) is associated with Donnai-Barrow syndrome (ClinVar).

How common is LRP2 p.Pro2278Ser (c.6832C>T) in the general population?

LRP2 p.Pro2278Ser (c.6832C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about LRP2 p.Pro2278Ser (c.6832C>T)?

AlphaMissense predicts likely pathogenic (score 0.5851) — an in-silico prediction, not a clinical call.

LRP2 p.Pro2278Ser

c.6832C>T · rs762578615 · VCV2101306

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.5851 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Conditions

Donnai-Barrow syndrome

Computational evidence

Protein change
AlphaMissense	0.5851	likely pathogenic
REVEL	0.621	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.2, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 156 kb · p 7.9e-06 · regional, not allelic
Overall
CADD	23.8	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 0.0011% South Asian · 1/91,072 alleles

Overall 0.000124% 2/1,614,084 alleles · very rare exomes 2/1,461,876 · genomes 0/152,208 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,072
European (non-Finnish)	8.47e-05%	1,180,013

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.Pro2278Ser
Coding: c.6832C>T
MANE Select: NM_004525
dbSNP: rs762578615
Type: single nucleotide variant
Location: chr2:169206888 (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.Pro2278Leu 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-pro2278ser (accessed [today's date]).

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