Is LDLR p.Cys95= (c.285C>T) pathogenic?

LDLR p.Cys95= (c.285C>T) is classified Likely benign in LDLR (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-02-23). Ultra-rare (popmax 0.016%, afr); Associated with familial hypercholesterolemia.

What condition is associated with LDLR p.Cys95= (c.285C>T)?

LDLR p.Cys95= (c.285C>T) is associated with familial hypercholesterolemia, hypercholesterolemia, familial, 1 (ClinVar).

How common is LDLR p.Cys95= (c.285C>T) in the general population?

LDLR p.Cys95= (c.285C>T) is ultra-rare (popmax 0.016%, afr) (gnomAD).

LDLR p.Cys95=

c.285C>T · rs139400379 · VCV526763

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.016%, afr)

Conditions

familial hypercholesterolemia

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 -8.7	GERP -5.1
Overall
CADD	1.279	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.016% African / African-American · 12/74,918 alleles

Filtering AF 0.00921% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00722%

Overall 0.00217% 35/1,613,592 alleles · ultra-rare exomes 32/1,461,436 · genomes 3/152,156 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.016%	6,243
South Asian	0.00659%	15,181
East Asian	0.00223%	44,860
Remaining individualsnot grpmax-eligible	0.0016%	62,448
European (non-Finnish)	0.00127%	78,650

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.Cys95=
Coding: c.285C>T
MANE Select: NM_000527
dbSNP: rs139400379
Type: single nucleotide variant
Location: chr19:11102758 (GRCh38)
Gene constraint: LOEUF 1.091 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.81 · 36 PDB
Residue 95: a β-strand; a disulfide bond; the ldl-receptor class a 2 domain; a UniProt-annotated variant site (in fhcl1)

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

Disease context

familial hypercholesterolemia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hypercholesterolemia, familial, 1

Similar variants

LDLR p.Cys95Gly Likely pathogenic ★★★ same residue
LDLR p.Cys95Tyr Likely pathogenic ★★★ same residue
LDLR p.Cys95Arg Pathogenic/Likely pathogenic ★★ same residue
LDLR p.Cys95Phe Pathogenic/Likely pathogenic ★★ same residue
LDLR p.Cys95Ser Pathogenic/Likely pathogenic ★★ same residue
LDLR p.Cys95Ter Pathogenic ★★ same residue
LDLR p.Cys95Trp Pathogenic/Likely pathogenic ★★ 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-cys95 (accessed [today's date]).

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