Is LDLR p.Arg416Trp (c.1246C>T) pathogenic?

LDLR p.Arg416Trp (c.1246C>T) is classified Pathogenic/Likely pathogenic in LDLR (ClinVar, Multiple submitters, 31 submitters; last evaluated 2025-12-18). AlphaMissense: likely benign (0.261); Very rare (popmax 0.005%, amr); Associated with homozygous familial hypercholesterolemia.

What condition is associated with LDLR p.Arg416Trp (c.1246C>T)?

LDLR p.Arg416Trp (c.1246C>T) is associated with homozygous familial hypercholesterolemia, familial hypercholesterolemia, hypercholesterolemia, familial, 1 (ClinVar).

How common is LDLR p.Arg416Trp (c.1246C>T) in the general population?

LDLR p.Arg416Trp (c.1246C>T) is very rare (popmax 0.005%, amr) (gnomAD).

How is Homozygous familial hypercholesterolemia inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about LDLR p.Arg416Trp (c.1246C>T)?

AlphaMissense predicts likely benign (score 0.261) — an in-silico prediction, not a clinical call.

LDLR p.Arg416Trp

c.1246C>T · rs570942190 · VCV183110

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 31 submitters

AlphaMissense

likely benign

0.261 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

homozygous familial hypercholesterolemia

Computational evidence

Protein change
AlphaMissense	0.261	likely benign ⚠ discordant with ClinVar
REVEL	0.835	moderately pathogenic-leaning
SaProt	LLR -11.46	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.81	GERP -5.1, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 42 kb · p 0.91 · regional, not allelic
Overall
CADD	26.1	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 0.005% Admixed American · 3/59,968 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.000991% 16/1,613,778 alleles · very rare exomes 14/1,461,604 · genomes 2/152,174 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.005%	19,989
East Asian	0.00446%	22,432
South Asian	0.00329%	30,357
Remaining individualsnot grpmax-eligible	0.0016%	62,490
European (non-Finnish)	0.000593%	168,574

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: LDLR
Protein: p.Arg416Trp
Coding: c.1246C>T
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

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

Also linked: familial hypercholesterolemia hypercholesterolemia, familial, 1

For Homozygous familial hypercholesterolemia (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Neonatal
Prevalence: 1-9 / 1 000 000 (Japan)

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.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-arg416trp (accessed [today's date]).

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