Is LRP4 p.Arg431His (c.1292G>A) pathogenic?

LRP4 p.Arg431His (c.1292G>A) is classified Uncertain significance in LRP4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-18). AlphaMissense: likely benign (0.172); Ultra-rare (popmax 0.0133%, amr); Associated with Inborn genetic diseases.

What condition is associated with LRP4 p.Arg431His (c.1292G>A)?

LRP4 p.Arg431His (c.1292G>A) is associated with Inborn genetic diseases (ClinVar).

How common is LRP4 p.Arg431His (c.1292G>A) in the general population?

LRP4 p.Arg431His (c.1292G>A) is ultra-rare (popmax 0.0133%, amr) (gnomAD).

What do computational predictors say about LRP4 p.Arg431His (c.1292G>A)?

AlphaMissense predicts likely benign (score 0.172) — an in-silico prediction, not a clinical call.

LRP4 p.Arg431His

c.1292G>A · VCV3868220

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.172 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0133%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.172	likely benign
REVEL	0.704	pathogenic-leaning
SaProt	LLR -6.04	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP -0.1, phastCons 1
Overall
CADD	33.0	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 0.0133% Admixed American · 8/60,000 alleles

Filtering AF 0.00661% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00482%

Overall 0.00167% 27/1,613,900 alleles · ultra-rare exomes 23/1,461,704 · genomes 4/152,196 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0133%	7,500
South Asian	0.00659%	15,181
East Asian	0.00223%	44,898
Remaining individualsnot grpmax-eligible	0.0016%	62,484
European (non-Finnish)	0.000932%	107,276

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.Arg431His
Coding: c.1292G>A
MANE Select: NM_002334
Type: single nucleotide variant
Location: chr11:46895183 (GRCh38)
Gene constraint: LOEUF 0.501 · pLI 0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.57 · 1 PDB
Residue 431: the egf-like 2; calcium-binding domain

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

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LRP4 p.Arg1194Trp Uncertain significance ★★ ⚠ same condition
LRP4 p.Arg1425Gln Uncertain significance ★★ ⚠ same condition
LRP4 p.Arg1506Trp Uncertain significance ★★ ⚠ same condition
LRP4 p.Arg202His Uncertain significance ★★ ⚠ same condition
LRP4 p.Arg232Cys Uncertain significance ★★ ⚠ same condition
LRP4 p.Arg249His 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-arg431his (accessed [today's date]).

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