Is LDLR p.Arg751Trp (c.2251C>T) pathogenic?

LDLR p.Arg751Trp (c.2251C>T) is classified Likely benign in LDLR (ClinVar, Expert panel, 6 submitters; last evaluated 2022-05-26). AlphaMissense: likely benign (0.1143); Very rare (popmax 0.004%, afr); Associated with hypercholesterolemia, familial, 1.

What condition is associated with LDLR p.Arg751Trp (c.2251C>T)?

LDLR p.Arg751Trp (c.2251C>T) is associated with hypercholesterolemia, familial, 1, familial hypercholesterolemia (ClinVar).

How common is LDLR p.Arg751Trp (c.2251C>T) in the general population?

LDLR p.Arg751Trp (c.2251C>T) is very rare (popmax 0.004%, afr) (gnomAD).

What do computational predictors say about LDLR p.Arg751Trp (c.2251C>T)?

AlphaMissense predicts likely benign (score 0.1143) — an in-silico prediction, not a clinical call.

LDLR p.Arg751Trp

c.2251C>T · rs756864388 · VCV926358

Likely benign Expert panel

Classification

Likely benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.1143 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.004%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hypercholesterolemia, familial, 1

ClinGen expert panel — Familial Hypercholesterolemia VCEP

Likely Benign for hypercholesterolemia, familial. Applied ACMG criteria (verbatim):

PM2 BS2 BP4

Curation rationale (ClinGen, verbatim)

NM_000527.5(LDLR): c.2251C>T (p.Arg751Trp) variant is classified as Likely benign for Familial Hypercholesterolemia by applying evidence codes PM2, BS2 and BP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2 - PopMax MAF = 0.0001202 (0.01202%) in African/African American exomes+genomes (gnomAD v2.1.1). BP4 - REVEL = 0.428, it is below 0.50, splicing evaluation required. Variant is exonic and at least 50bp downstream from canonical donor site, but it does not create AG/GT. BS2 - Variant identified in 717 heterozygotes and 72 homozygotes (PMID: 25414273). These subjects had the same level of LDLc as non-carriers (N=2408).

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
AlphaMissense	0.1143	likely benign
REVEL	0.428	indeterminate
SaProt	LLR -8.62	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.1	GERP -2.4
Regional constraint	o/e 1.00	unconstrained · MANE · 42 kb · p 0.91 · regional, not allelic
Overall
CADD	5.407	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 0.004% African / African-American · 3/74,938 alleles

Filtering AF 0.00299% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00267%

Overall 0.00322% 52/1,613,990 alleles · very rare exomes 45/1,461,802 · genomes 7/152,188 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.004%	24,979
European (non-Finnish)	0.0039%	25,652
Remaining individualsnot grpmax-eligible	0.0032%	31,244
Admixed American	0.00167%	59,958

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.Arg751Trp
Coding: c.2251C>T
MANE Select: NM_000527
dbSNP: rs756864388
Type: single nucleotide variant
Location: chr19:11123284 (GRCh38)
Gene constraint: LOEUF 1.091 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.81 · 36 PDB
Residue 751: 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.Arg751Gln Uncertain significance ★★★ ⚠ same residue
LDLR p.Arg751fs Pathogenic same residue
LDLR p.Arg751= 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
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-arg751trp (accessed [today's date]).

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