Is LRP4 p.Ala697Val (c.2090C>T) pathogenic?

LRP4 p.Ala697Val (c.2090C>T) is classified Uncertain significance in LRP4 (ClinVar, Single submitter, 2 submitters; last evaluated 2023-10-27). AlphaMissense: likely benign (0.0934); Very rare (popmax 0.00267%, afr); Associated with Cenani-Lenz syndactyly syndrome.

What condition is associated with LRP4 p.Ala697Val (c.2090C>T)?

LRP4 p.Ala697Val (c.2090C>T) is associated with Cenani-Lenz syndactyly syndrome, sclerosteosis 2, congenital myasthenic syndrome 17 (ClinVar).

How common is LRP4 p.Ala697Val (c.2090C>T) in the general population?

LRP4 p.Ala697Val (c.2090C>T) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about LRP4 p.Ala697Val (c.2090C>T)?

AlphaMissense predicts likely benign (score 0.0934) — an in-silico prediction, not a clinical call.

LRP4 p.Ala697Val

c.2090C>T · rs1002301696 · VCV2932951

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0934 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Cenani-Lenz syndactyly syndrome

Computational evidence

Protein change
AlphaMissense	0.0934	likely benign
REVEL	0.322	indeterminate
SaProt	LLR -4.91	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.77	gain · loss 0.46 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 10	GERP 0.93, phastCons 1
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00267% African / African-American · 2/75,024 alleles

Filtering AF 0.000442% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000186% 3/1,614,140 alleles · very rare exomes 3/1,461,886 · genomes 0/152,254 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,512
East Asian	0.00223%	44,872

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.Ala697Val
Coding: c.2090C>T
MANE Select: NM_002334
dbSNP: rs1002301696
Type: single nucleotide variant
Location: chr11:46889946 (GRCh38)
Gene constraint: LOEUF 0.501 · pLI 0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.57 · 1 PDB

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

Disease context

Cenani-Lenz syndactyly syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: sclerosteosis 2 congenital myasthenic syndrome 17

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-ala697val (accessed [today's date]).

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