Is LDLR p.Cys27= (c.81C>T) pathogenic?

LDLR p.Cys27= (c.81C>T) is classified Benign in LDLR (ClinVar, Multiple submitters, 21 submitters; last evaluated 2026-02-04). Common (popmax 12.3%, nfe) — too common for a highly-penetrant pathogenic allele; Associated with Cardiovascular phenotype.

What condition is associated with LDLR p.Cys27= (c.81C>T)?

LDLR p.Cys27= (c.81C>T) is associated with Cardiovascular phenotype, familial hypercholesterolemia, hypercholesterolemia, familial, 1 (ClinVar).

LDLR p.Cys27=

Q: How common is LDLR p.Cys27= (c.81C>T) in the general population?

LDLR p.Cys27= (c.81C>T) is common (popmax 12.3%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.81C>T · rs2228671 · VCV251010

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 21 submitters

gnomAD v4.1

Common

common (popmax 12.3%, nfe) — too common for a highly-penetrant pathogenic allele

Conditions

Cardiovascular phenotype

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 -1.1	GERP -4.8
Overall
CADD	7.644	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 12.3% European (non-Finnish) · 145,337/1,179,568 alleles

Filtering AF 12.3% ClinGen BA1/BS1 input FAF95, joint · FAF99 12.2%

Overall 10.9% 175,912/1,612,538 alleles · common

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	12.3%	8
Finnishnot grpmax-eligible	10.7%	9
Remaining individualsnot grpmax-eligible	10.2%	10
Middle Eastern	10%	10
Amishnot grpmax-eligible	9.76%	10
Ashkenazi Jewishnot grpmax-eligible	9.51%	11
Admixed American	7.22%	14
South Asian	7.13%	14
African / African-American	3.78%	26
East Asian	0.642%	156

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.Cys27=
Coding: c.81C>T
MANE Select: NM_000527
dbSNP: rs2228671
Type: single nucleotide variant
Location: chr19:11100236 (GRCh38)
Gene constraint: LOEUF 1.091 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.81 · 36 PDB
Residue 27: a disulfide bond; the ldl-receptor class a 1 domain; a UniProt-annotated variant site (in fhcl1; pathogenic; san francisco)

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 Smith-Lemli-Opitz syndrome

Similar variants

LDLR p.Cys27Trp Pathogenic ★★★ same residue
LDLR p.Cys27Arg Pathogenic/Likely pathogenic ★★ same residue
LDLR p.Cys27Ter Pathogenic/Likely pathogenic ★★ same residue
LDLR p.Cys27Tyr Conflicting classifications of pathogenicity ★ ⚠ same residue
LDLR p.Cys27fs Likely 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-cys27 (accessed [today's date]).

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