Is LDLR p.Asp227= (c.681C>T) pathogenic?

LDLR p.Asp227= (c.681C>T) is classified Likely benign in LDLR (ClinVar, Multiple submitters, 8 submitters; last evaluated 2025-12-11). Ultra-rare (popmax 0.0348%, afr); Associated with hypercholesterolemia, familial, 1.

What condition is associated with LDLR p.Asp227= (c.681C>T)?

LDLR p.Asp227= (c.681C>T) is associated with hypercholesterolemia, familial, 1, familial hypercholesterolemia (ClinVar).

How common is LDLR p.Asp227= (c.681C>T) in the general population?

LDLR p.Asp227= (c.681C>T) is ultra-rare (popmax 0.0348%, afr) (gnomAD).

LDLR p.Asp227=

c.681C>T · rs121908028 · VCV440595

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0348%, afr)

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 -5.3	GERP -5.1
Overall
CADD	7.554	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0348% African / African-American · 26/74,718 alleles

Filtering AF 0.0243% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0209%

Overall 0.00492% 79/1,605,286 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0348%	2,874
South Asian	0.0231%	4,330
Middle Eastern	0.0179%	5,574
East Asian	0.0179%	5,582
Remaining individualsnot grpmax-eligible	0.00484%	20,669
Admixed American	0.00334%	29,927
European (non-Finnish)	0.00153%	65,223

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.Asp227=
Coding: c.681C>T
MANE Select: NM_000527
dbSNP: rs121908028
Type: single nucleotide variant
Location: chr19:11105587 (GRCh38)
Gene constraint: LOEUF 1.091 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.81 · 36 PDB
Residue 227: a UniProt-annotated variant site (in fhcl1; afrikaner-1/maine; 65-70% of afrikaner americans); the 'binding to getah virus e1-e2 spike glycoproteins' region; an α-helix; a disulfide bond; 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.Asp227Glu Pathogenic ★★★ same residue
LDLR p.Asp227Val Pathogenic/Likely pathogenic ★★ same residue
LDLR p.Asp227Asn Likely pathogenic ★ same residue
LDLR p.Asp227His Conflicting classifications of pathogenicity ★ ⚠ same residue
LDLR p.Asp227Gly Pathogenic same residue
LDLR p.Asp227_Glu228insCysLysAspLysSerAsp Pathogenic/Likely pathogenic ★★ same residue
LDLR p.Asp227del Pathogenic/Likely pathogenic ★★ same residue
LDLR p.Asp227_Glu228insSerGlyLysProAspCys Likely pathogenic ★ same residue

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-asp227 (accessed [today's date]).

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