Is LDLR p.Asp266Val (c.797A>T) pathogenic?

LDLR p.Asp266Val (c.797A>T) is classified Likely pathogenic in LDLR (ClinVar, Expert panel, 2 submitters; last evaluated 2021-11-14). AlphaMissense: likely pathogenic (0.9971); Absent from gnomAD v4.1; Associated with hypercholesterolemia, familial, 1.

What condition is associated with LDLR p.Asp266Val (c.797A>T)?

LDLR p.Asp266Val (c.797A>T) is associated with hypercholesterolemia, familial, 1 (ClinVar).

How common is LDLR p.Asp266Val (c.797A>T) in the general population?

LDLR p.Asp266Val (c.797A>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about LDLR p.Asp266Val (c.797A>T)?

AlphaMissense predicts likely pathogenic (score 0.9971) — an in-silico prediction, not a clinical call.

LDLR p.Asp266Val

c.797A>T · rs879254678 · VCV251458

Likely pathogenic Expert panel

Classification

Likely pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9971 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hypercholesterolemia, familial, 1

ClinGen expert panel — Familial Hypercholesterolemia VCEP

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

PM2 PM5_Strong PP3

Curation rationale (ClinGen, verbatim)

The NM_000527.5(LDLR): c.797A>T (p.Asp266Val) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes PM5_Strong, PM2, and PP3 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). PM5_Strong - 4 other missense variants in the same codon: - NM_000527.5(LDLR): c.796G>T (p.Asp266Asn) (ClinVar ID 226334) - Pathogenic by these guidelines, - NM_000527.5(LDLR): c.797A>G (p.Asp266Gly) (ClinVar ID 251458) – Likely pathogenic by these guidelines, - NM_000527.5(LDLR): c.796A>T (p.Asp266Tyr) (ClinVar ID 251456) – Pathogenic by these guidelines, - NM_000527.5(LDLR): c.798T>A (p.Asp266Glu) - (ClinVar ID 161287) - Pathogenic by these guidelines. There are 3 variants in the same codon classified as Pathogenic by these guidelines; PM2 - This variant is absent from gnomAD (gnomAD v2.1.1); PP3 - REVEL = 0.97;

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

Computational evidence

Protein change
AlphaMissense	0.9971	likely pathogenic ✓ concordant with ClinVar · top 1% in LDLR
REVEL	0.974	strongly pathogenic-leaning
SaProt	LLR -15.69	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 11	GERP 1.9, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 42 kb · p 0.91 · regional, not allelic
Overall
CADD	25.1	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

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.Asp266Val
Coding: c.797A>T
MANE Select: NM_000527
dbSNP: rs879254678
Type: single nucleotide variant
Location: chr19:11106667 (GRCh38)
Gene constraint: LOEUF 1.091 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.81 · 36 PDB
Residue 266: the ldl-receptor class a 6 domain; a UniProt-annotated variant site (in fhcl1; pathogenic; cincinnati-1); 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

Similar variants

LDLR p.Asp266Asn Pathogenic ★★★ same residue
LDLR p.Asp266Glu Pathogenic ★★★ same residue
LDLR p.Asp266Gly Likely pathogenic ★★★ same residue
LDLR p.Asp266Tyr Pathogenic ★★★ same residue
LDLR p.Asp266His Pathogenic/Likely pathogenic ★★ same residue
LDLR p.Asp266fs Pathogenic ★ same residue
LDLR p.Asp266= Likely benign ★ same residue
LDLR c.1186+5G>A 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-asp266val (accessed [today's date]).

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