Is LRP4 p.Ser87Phe (c.260C>T) pathogenic?

LRP4 p.Ser87Phe (c.260C>T) is classified Uncertain significance in LRP4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-13). AlphaMissense: ambiguous (0.5339); Very rare (popmax 0.00667%, afr); Associated with congenital myasthenic syndrome 17.

What condition is associated with LRP4 p.Ser87Phe (c.260C>T)?

LRP4 p.Ser87Phe (c.260C>T) is associated with congenital myasthenic syndrome 17, Cenani-Lenz syndactyly syndrome, sclerosteosis 2 (ClinVar).

How common is LRP4 p.Ser87Phe (c.260C>T) in the general population?

LRP4 p.Ser87Phe (c.260C>T) is very rare (popmax 0.00667%, afr) (gnomAD).

What do computational predictors say about LRP4 p.Ser87Phe (c.260C>T)?

AlphaMissense predicts ambiguous (score 0.5339) — an in-silico prediction, not a clinical call.

LRP4 p.Ser87Phe

c.260C>T · VCV3599753

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5339 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00667%, afr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

congenital myasthenic syndrome 17

Computational evidence

Protein change
AlphaMissense	0.5339	ambiguous
REVEL	0.787	moderately pathogenic-leaning
SaProt	LLR -9.21	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 0.89, phastCons 1
Overall
CADD	28.4	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00667% African / African-American · 5/74,930 alleles

Filtering AF 0.00255% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00161%

Overall 0.000372% 6/1,614,022 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00667%	14,986
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: LRP4
Protein: p.Ser87Phe
Coding: c.260C>T
MANE Select: NM_002334
Type: single nucleotide variant
Location: chr11:46900318 (GRCh38)
Gene constraint: LOEUF 0.501 · pLI 0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.57 · 1 PDB
Residue 87: a disulfide bond; the ldl-receptor class a 2 domain

Full LRP4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

congenital myasthenic syndrome 17 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Cenani-Lenz syndactyly syndrome sclerosteosis 2

Similar variants

LRP4 c.316+1G>A Pathogenic ★★ same condition
LRP4 c.547+1G>A Likely pathogenic ★★ same condition
LRP4 p.Gln944Ter Pathogenic ★★ same condition
LRP4 p.Glu1233Ala Pathogenic/Likely pathogenic ★★ ⚠ same condition
LRP4 c.1309+6G>T Uncertain significance ★★ same condition
LRP4 c.2215+5G>A Uncertain significance ★★ same condition
LRP4 c.2216-3C>T Uncertain significance ★★ same condition
LRP4 c.3277+5G>T Uncertain significance ★★ 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/lrp4-p-ser87phe (accessed [today's date]).

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