Is LDLR p.Cys216Phe (c.647G>T) pathogenic?

LDLR p.Cys216Phe (c.647G>T) is classified Conflicting classifications of pathogenicity in LDLR (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2023-06-28). AlphaMissense: likely pathogenic (0.9809); Absent from gnomAD v4.1; Associated with hypercholesterolemia, familial, 1.

What condition is associated with LDLR p.Cys216Phe (c.647G>T)?

LDLR p.Cys216Phe (c.647G>T) is associated with hypercholesterolemia, familial, 1 (ClinVar).

How common is LDLR p.Cys216Phe (c.647G>T) in the general population?

LDLR p.Cys216Phe (c.647G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about LDLR p.Cys216Phe (c.647G>T)?

AlphaMissense predicts likely pathogenic (score 0.9809) — an in-silico prediction, not a clinical call.

LDLR p.Cys216Phe

c.647G>T · rs879254611 · VCV251347

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9809 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hypercholesterolemia, familial, 1

Computational evidence

Protein change
AlphaMissense	0.9809	likely pathogenic · top 9% in LDLR
REVEL	0.951	strongly pathogenic-leaning
SaProt	LLR -16.82	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.5, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 42 kb · p 0.91 · regional, not allelic
Overall
CADD	25.6	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.Cys216Phe
Coding: c.647G>T
MANE Select: NM_000527
dbSNP: rs879254611
Type: single nucleotide variant
Location: chr19:11105553 (GRCh38)
Gene constraint: LOEUF 1.091 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.81 · 36 PDB
Residue 216: the 'binding to getah virus e1-e2 spike glycoproteins' region; 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

Similar variants

LDLR p.Cys216Arg Pathogenic/Likely pathogenic ★★ same residue
LDLR p.Cys216Tyr Pathogenic/Likely pathogenic ★★ same residue
LDLR p.Cys216_Asp217delinsTer Pathogenic ★★ same residue
LDLR p.Cys216fs Pathogenic ★★ same residue
LDLR p.Cys216Trp 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-cys216phe (accessed [today's date]).

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