Is LDLR p.Arg416Pro (c.1247G>C) pathogenic?

LDLR p.Arg416Pro (c.1247G>C) is classified Likely pathogenic in LDLR (ClinVar, Multiple submitters, 5 submitters; last evaluated 2024-10-02). AlphaMissense: likely pathogenic (0.6373); Absent from gnomAD v4.1; Associated with familial hypercholesterolemia.

What condition is associated with LDLR p.Arg416Pro (c.1247G>C)?

LDLR p.Arg416Pro (c.1247G>C) is associated with familial hypercholesterolemia, hypercholesterolemia, familial, 1 (ClinVar).

How common is LDLR p.Arg416Pro (c.1247G>C) in the general population?

LDLR p.Arg416Pro (c.1247G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about LDLR p.Arg416Pro (c.1247G>C)?

AlphaMissense predicts likely pathogenic (score 0.6373) — an in-silico prediction, not a clinical call.

LDLR p.Arg416Pro

c.1247G>C · rs773658037 · VCV251753

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.6373 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

familial hypercholesterolemia

Computational evidence

Protein change
AlphaMissense	0.6373	likely pathogenic ✓ concordant with ClinVar
REVEL	0.839	moderately pathogenic-leaning
SaProt	LLR -12.08	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP 1.5, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 42 kb · p 0.91 · regional, not allelic
Overall
CADD	25.4	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

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.Arg416Pro
Coding: c.1247G>C
MANE Select: NM_000527
dbSNP: rs773658037
Type: single nucleotide variant
Location: chr19:11113338 (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

Also linked: hypercholesterolemia, familial, 1

Similar variants

LDLR p.Arg416Gln Pathogenic/Likely pathogenic ★★ ⚠ same residue
LDLR p.Arg416Leu Likely pathogenic ★★ ⚠ same residue
LDLR p.Arg416Trp Pathogenic/Likely pathogenic ★★ ⚠ same residue
LDLR p.Arg416= Likely benign ★ 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.1705+2T>C 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-arg416pro (accessed [today's date]).

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