Is LDLR p.Arg744Ter (c.2230C>T) pathogenic?

LDLR p.Arg744Ter (c.2230C>T) is classified Pathogenic in LDLR (ClinVar, Multiple submitters, 10 submitters; last evaluated 2026-06-30). Ultra-rare (popmax 0.0183%, amr); Associated with hypercholesterolemia, familial, 1.

What condition is associated with LDLR p.Arg744Ter (c.2230C>T)?

LDLR p.Arg744Ter (c.2230C>T) is associated with hypercholesterolemia, familial, 1, familial hypercholesterolemia (ClinVar).

How common is LDLR p.Arg744Ter (c.2230C>T) in the general population?

LDLR p.Arg744Ter (c.2230C>T) is ultra-rare (popmax 0.0183%, amr) (gnomAD).

LDLR p.Arg744Ter

c.2230C>T · rs200793488 · VCV430795

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 10 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0183%, amr)

Conditions

hypercholesterolemia, familial, 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	predicted	premature termination codon in exon 15 of 18
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.091	GERP -1.9
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0183% Admixed American · 11/59,980 alleles

Filtering AF 0.0102% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00786%

Overall 0.000805% 13/1,614,012 alleles · ultra-rare exomes 11/1,461,740 · genomes 2/152,272 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0183%	5,453
Remaining individualsnot grpmax-eligible	0.0016%	62,502
European (non-Finnish)	8.47e-05%	1,179,952

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.Arg744Ter
Coding: c.2230C>T
MANE Select: NM_000527
dbSNP: rs200793488
Type: single nucleotide variant
Location: chr19:11123263 (GRCh38)
Gene constraint: LOEUF 1.091 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.81 · 36 PDB
Residue 744: the 'clustered o-linked oligosaccharides' region; the 'disordered' region

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

Disease context

hypercholesterolemia, familial, 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: familial hypercholesterolemia

Similar variants

LDLR p.Arg744= Benign ★★ same residue
LDLR p.Arg744Gln Uncertain significance ★★★ same residue
LDLR p.Arg744fs Pathogenic/Likely pathogenic ★★ same residue
LDLR p.Arg744Trp Uncertain significance ★★ same residue
LDLR p.Arg744_Pro745dup Conflicting classifications of pathogenicity ★ 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

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-arg744ter (accessed [today's date]).

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