Is LDLR p.Asp217= (c.651T>C) pathogenic?

LDLR p.Asp217= (c.651T>C) is classified Likely benign in LDLR (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-10-11). Ultra-rare (popmax 0.0358%, eas); Associated with hypercholesterolemia, familial, 1.

What condition is associated with LDLR p.Asp217= (c.651T>C)?

LDLR p.Asp217= (c.651T>C) is associated with hypercholesterolemia, familial, 1, familial hypercholesterolemia (ClinVar).

How common is LDLR p.Asp217= (c.651T>C) in the general population?

LDLR p.Asp217= (c.651T>C) is ultra-rare (popmax 0.0358%, eas) (gnomAD).

LDLR p.Asp217=

c.651T>C · rs201374693 · VCV700092

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0358%, eas)

Conditions

hypercholesterolemia, familial, 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -5.7	GERP -5.1
Overall
CADD	0.823	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0358% East Asian · 16/44,720 alleles

Filtering AF 0.0224% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0182%

Overall 0.00118% 19/1,610,928 alleles · ultra-rare exomes 15/1,459,014 · genomes 4/151,914 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0358%	2,795
African / African-American	0.00267%	37,454
European (non-Finnish)	8.49e-05%	1,178,464

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.Asp217=
Coding: c.651T>C
MANE Select: NM_000527
dbSNP: rs201374693
Type: single nucleotide variant
Location: chr19:11105557 (GRCh38)
Gene constraint: LOEUF 1.091 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.81 · 36 PDB
Residue 217: the 'binding to getah virus e1-e2 spike glycoproteins' region; a β-strand; the ldl-receptor class a 5 domain

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.Asp217Gly Uncertain significance ★★ ⚠ same residue
LDLR p.Asp217Val Uncertain significance ★ ⚠ same residue
LDLR p.Asp217_Gly219del Likely pathogenic ★★ same residue
LDLR p.Asp217Ter Pathogenic/Likely pathogenic ★★ same residue
LDLR p.Asp217fs Pathogenic ★ 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-asp217 (accessed [today's date]).

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