Is LDLR p.Cys95Phe (c.284G>T) pathogenic?

LDLR p.Cys95Phe (c.284G>T) is classified Pathogenic/Likely pathogenic in LDLR (ClinVar, Multiple submitters, 5 submitters; last evaluated 2022-09-20). AlphaMissense: likely pathogenic (0.9926); Absent from gnomAD v4.1; Associated with Cardiovascular phenotype.

What condition is associated with LDLR p.Cys95Phe (c.284G>T)?

LDLR p.Cys95Phe (c.284G>T) is associated with Cardiovascular phenotype, familial hypercholesterolemia, hypercholesterolemia, familial, 1 (ClinVar).

How common is LDLR p.Cys95Phe (c.284G>T) in the general population?

LDLR p.Cys95Phe (c.284G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about LDLR p.Cys95Phe (c.284G>T)?

AlphaMissense predicts likely pathogenic (score 0.9926) — an in-silico prediction, not a clinical call.

LDLR p.Cys95Phe

c.284G>T · rs879254457 · VCV251114

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.9926 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.9926	likely pathogenic ✓ concordant with ClinVar · top 4% in LDLR
REVEL	0.93	moderately pathogenic-leaning
SaProt	LLR -14.11	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 11	GERP 2.5, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 42 kb · p 0.91 · regional, not allelic
Overall
CADD	26.4	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: LDLR
Protein: p.Cys95Phe
Coding: c.284G>T
MANE Select: NM_000527
dbSNP: rs879254457
Type: single nucleotide variant
Location: chr19:11102757 (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

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

Also linked: familial hypercholesterolemia 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.Cys95Ser Pathogenic/Likely pathogenic ★★ same residue
LDLR p.Cys95Ter Pathogenic ★★ same residue
LDLR p.Cys95Trp Pathogenic/Likely pathogenic ★★ same residue
LDLR p.Cys95= Likely benign ★★ 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-cys95phe (accessed [today's date]).

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