Is LDLR p.Cys276= (c.828C>T) pathogenic?

LDLR p.Cys276= (c.828C>T) is classified Benign/Likely benign in LDLR (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-01-26). Rare (popmax 0.31%, afr); Associated with Cardiovascular phenotype.

What condition is associated with LDLR p.Cys276= (c.828C>T)?

LDLR p.Cys276= (c.828C>T) is associated with Cardiovascular phenotype, familial hypercholesterolemia, hypercholesterolemia, familial, 1 (ClinVar).

How common is LDLR p.Cys276= (c.828C>T) in the general population?

LDLR p.Cys276= (c.828C>T) is rare (popmax 0.31%, afr) (gnomAD).

LDLR p.Cys276=

c.828C>T · rs146651743 · VCV440606

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

rare (popmax 0.31%, afr)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -14	GERP -3.7
Overall
CADD	0.463	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.31% African / African-American · 232/74,936 alleles

Filtering AF 0.277% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.264%

Overall 0.0163% 263/1,610,812 alleles · rare exomes 131/1,458,586 · genomes 132/152,226 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.31%	323
Remaining individualsnot grpmax-eligible	0.0225%	4,447
Middle Eastern	0.0165%	6,044
Admixed American	0.0134%	7,480
South Asian	0.0011%	91,026
European (non-Finnish)	0.000594%	168,267

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.Cys276=
Coding: c.828C>T
MANE Select: NM_000527
dbSNP: rs146651743
Type: single nucleotide variant
Location: chr19:11107402 (GRCh38)
Gene constraint: LOEUF 1.091 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.81 · 36 PDB
Residue 276: the ldl-receptor class a 7 domain; a UniProt-annotated variant site (in fhcl1); a UniProt-annotated variant site (in fhcl1; uncertain significance); a disulfide bond

Full LDLR gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: familial hypercholesterolemia hypercholesterolemia, familial, 1

Similar variants

LDLR p.Cys276Arg Likely pathogenic ★★★ same residue
LDLR p.Cys276Ter Pathogenic ★★★ same residue
LDLR p.Cys276Gly Likely pathogenic ★★ same residue
LDLR p.Cys276Trp Pathogenic/Likely pathogenic ★★ same residue
LDLR p.Cys276Tyr Likely pathogenic ★★ same residue
LDLR p.Cys276fs Pathogenic ★★ same residue
LDLR c.1186+5G>A Likely pathogenic ★★★ same condition
LDLR c.1359-1G>A 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-cys276 (accessed [today's date]).

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