Is LRP2 p.Ser3104= (c.9312C>T) pathogenic?

LRP2 p.Ser3104= (c.9312C>T) is classified Likely benign in LRP2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-20). Ultra-rare (popmax 0.0692%, sas); Associated with Donnai-Barrow syndrome.

What condition is associated with LRP2 p.Ser3104= (c.9312C>T)?

LRP2 p.Ser3104= (c.9312C>T) is associated with Donnai-Barrow syndrome (ClinVar).

How common is LRP2 p.Ser3104= (c.9312C>T) in the general population?

LRP2 p.Ser3104= (c.9312C>T) is ultra-rare (popmax 0.0692%, sas) (gnomAD).

LRP2 p.Ser3104=

c.9312C>T · rs538919316 · VCV1597214

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0692%, 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 -0.82	GERP -4.5
Overall
CADD	5.489	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0692% South Asian · 63/91,060 alleles

Filtering AF 0.0554% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0505%

Overall 0.00725% 117/1,613,934 alleles · ultra-rare exomes 102/1,461,848 · genomes 15/152,086 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0692%	1,445
Remaining individualsnot grpmax-eligible	0.008%	12,500
African / African-American	0.00667%	14,989
Admixed American	0.005%	19,999
East Asian	0.00446%	22,434
European (non-Finnish)	0.00331%	30,256

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.Ser3104=
Coding: c.9312C>T
MANE Select: NM_004525
dbSNP: rs538919316
Type: single nucleotide variant
Location: chr2:169187986 (GRCh38)
Gene constraint: LOEUF 0.352 · pLI 1.00 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 3104: the ldl-receptor class a 25 domain; 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 p.Ser3104Asn Conflicting classifications of pathogenicity ★ ⚠ 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-ser3104 (accessed [today's date]).

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