Is LDLR p.Arg253Trp (c.757C>T) pathogenic?

LDLR p.Arg253Trp (c.757C>T) is classified Uncertain significance in LDLR (ClinVar, Expert panel, 18 submitters; last evaluated 2021-06-07). AlphaMissense: likely benign (0.1416); Rare (popmax 0.124%, afr); Associated with hypercholesterolemia, familial, 1.

What condition is associated with LDLR p.Arg253Trp (c.757C>T)?

LDLR p.Arg253Trp (c.757C>T) is associated with hypercholesterolemia, familial, 1, familial hypercholesterolemia (ClinVar).

How common is LDLR p.Arg253Trp (c.757C>T) in the general population?

LDLR p.Arg253Trp (c.757C>T) is rare (popmax 0.124%, afr) (gnomAD).

What do computational predictors say about LDLR p.Arg253Trp (c.757C>T)?

AlphaMissense predicts likely benign (score 0.1416) — an in-silico prediction, not a clinical call.

LDLR p.Arg253Trp

c.757C>T · rs150673992 · VCV161261

Uncertain significance Expert panel

Classification

Uncertain significance

ClinVar

Review

Expert panel ★★★☆

ClinVar · 18 submitters

AlphaMissense

likely benign

0.1416 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.124%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hypercholesterolemia, familial, 1

ClinGen expert panel

Uncertain Significance — Familial Hypercholesterolemia VCEP (hypercholesterolemia, familial).

Computational evidence

Protein change
AlphaMissense	0.1416	likely benign
REVEL	0.689	pathogenic-leaning
SaProt	LLR -3.85	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.7	GERP -2.8, phastCons 0.98
Regional constraint	o/e 1.00	unconstrained · MANE · 42 kb · p 0.91 · regional, not allelic
Overall
CADD	24.4	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

Grpmax group 0.124% African / African-American · 93/75,046 alleles

Filtering AF 0.103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.096%

Overall 0.0155% 251/1,614,162 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.124%	807
South Asian	0.0264%	3,795
Remaining individualsnot grpmax-eligible	0.0208%	4,808
Admixed American	0.0167%	6,001
European (non-Finnish)	0.00932%	10,728
East Asian	0.00223%	44,884

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.Arg253Trp
Coding: c.757C>T
MANE Select: NM_000527
dbSNP: rs150673992
Type: single nucleotide variant
Location: chr19:11106627 (GRCh38)
Gene constraint: LOEUF 1.091 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.81 · 36 PDB
Residue 253: the ldl-receptor class a 6 domain; a UniProt-annotated variant site (in fhcl1; uncertain significance); an α-helix

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.Arg253Gln Uncertain significance ★★★ ⚠ same residue
LDLR p.Arg253Pro Uncertain significance ★★★ ⚠ same residue
LDLR p.Arg253Gly Uncertain significance ★ ⚠ same residue
LDLR p.Arg253= 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-arg253trp (accessed [today's date]).

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