Is LRP2 p.Ser3145Phe (c.9434C>T) pathogenic?

LRP2 p.Ser3145Phe (c.9434C>T) is classified Uncertain significance in LRP2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-11-30). AlphaMissense: likely benign (0.1723); Very rare (popmax 0.00934%, afr).

How common is LRP2 p.Ser3145Phe (c.9434C>T) in the general population?

LRP2 p.Ser3145Phe (c.9434C>T) is very rare (popmax 0.00934%, afr) (gnomAD).

What do computational predictors say about LRP2 p.Ser3145Phe (c.9434C>T)?

AlphaMissense predicts likely benign (score 0.1723) — an in-silico prediction, not a clinical call.

LRP2 p.Ser3145Phe

c.9434C>T · rs200487069 · VCV1974802

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1723 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00934%, afr)

Missense predictors

1/2 damaging

AlphaMissense, REVEL · SaProt no call

Computational evidence

Protein change
AlphaMissense	0.1723	likely benign
REVEL	0.685	pathogenic-leaning
SaProt	—	not scored · why
⇒ REVEL calls this damaging; AlphaMissense does not; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.6, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 30 kb · p 2.4e-10 · regional, not allelic
Overall
CADD	23.3	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 0.00934% African / African-American · 7/74,976 alleles

Filtering AF 0.00437% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00309%

Overall 0.000682% 11/1,613,960 alleles · very rare exomes 8/1,461,798 · genomes 3/152,162 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00934%	10,711
South Asian	0.0033%	30,349
European (non-Finnish)	8.47e-05%	1,179,972

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.Ser3145Phe
Coding: c.9434C>T
MANE Select: NM_004525
dbSNP: rs200487069
Type: single nucleotide variant
Location: chr2:169185914 (GRCh38)
Gene constraint: LOEUF 0.352 · pLI 1.00 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 3145: the egf-like 3 domain

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

Similar variants

LRP2 c.12019+1G>A Likely pathogenic ★★ same type
LRP2 c.2639+1G>A Pathogenic/Likely pathogenic ★★ same type
LRP2 c.3667+1G>A Pathogenic/Likely pathogenic ★★ same type
LRP2 c.8452+1G>A Pathogenic ★★ same type
LRP2 p.Arg1953Ter Pathogenic/Likely pathogenic ★★ same type
LRP2 p.Arg2095Ter Pathogenic/Likely pathogenic ★★ same type
LRP2 p.Arg2225Ter Pathogenic/Likely pathogenic ★★ same type
LRP2 p.Arg233Ter Pathogenic ★★ same type

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-ser3145phe (accessed [today's date]).

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