Is LDLR p.Arg416= (c.1246C>A) pathogenic?

LDLR p.Arg416= (c.1246C>A) is classified Likely benign in LDLR (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-08). Absent from gnomAD v4.1; Associated with familial hypercholesterolemia.

What condition is associated with LDLR p.Arg416= (c.1246C>A)?

LDLR p.Arg416= (c.1246C>A) is associated with familial hypercholesterolemia (ClinVar).

How common is LDLR p.Arg416= (c.1246C>A) in the general population?

LDLR p.Arg416= (c.1246C>A) is absent from gnomAD v4.1 (gnomAD).

LDLR p.Arg416=

c.1246C>A · rs570942190 · VCV2723639

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

familial hypercholesterolemia

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 0.81	GERP -5.1, phastCons 1
Overall
CADD	8.136	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: LDLR
Protein: p.Arg416=
Coding: c.1246C>A
MANE Select: NM_000527
dbSNP: rs570942190
Type: single nucleotide variant
Location: chr19:11113337 (GRCh38)
Gene constraint: LOEUF 1.091 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.81 · 36 PDB
Residue 416: a UniProt-annotated variant site (in fhcl1; uncertain significance); a UniProt-annotated variant site (in fhcl1; results in reduced receptor expression at the cell surface due to defective receptor recycling)

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

Disease context

familial hypercholesterolemia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

LDLR p.Arg416Gln Pathogenic/Likely pathogenic ★★ ⚠ same residue
LDLR p.Arg416Leu Likely pathogenic ★★ ⚠ same residue
LDLR p.Arg416Pro Likely pathogenic ★★ same residue
LDLR p.Arg416Trp Pathogenic/Likely pathogenic ★★ ⚠ same residue
LDLR c.1186+5G>A Likely pathogenic ★★★ same condition
LDLR c.1359-1G>A Pathogenic ★★★ same condition
LDLR c.1359-5C>G Likely pathogenic ★★★ same condition
LDLR c.190+4A>T 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/ldlr-p-arg416 (accessed [today's date]).

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