Is LDLR p.Cys116Phe (c.347G>T) pathogenic?

LDLR p.Cys116Phe (c.347G>T) is classified Likely pathogenic in LDLR (ClinVar, Single submitter, 1 submitter; last evaluated 2016-03-25). AlphaMissense: likely pathogenic (0.9878); Absent from gnomAD v4.1; Associated with hypercholesterolemia, familial, 1.

What condition is associated with LDLR p.Cys116Phe (c.347G>T)?

LDLR p.Cys116Phe (c.347G>T) is associated with hypercholesterolemia, familial, 1 (ClinVar).

How common is LDLR p.Cys116Phe (c.347G>T) in the general population?

LDLR p.Cys116Phe (c.347G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about LDLR p.Cys116Phe (c.347G>T)?

AlphaMissense predicts likely pathogenic (score 0.9878) — an in-silico prediction, not a clinical call.

LDLR p.Cys116Phe

c.347G>T · rs879254485 · VCV251166

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9878 · 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	0.9878	likely pathogenic ✓ concordant with ClinVar · top 7% in LDLR
REVEL	0.933	strongly pathogenic-leaning
SaProt	LLR -15.44	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	27.2	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.Cys116Phe
Coding: c.347G>T
MANE Select: NM_000527
dbSNP: rs879254485
Type: single nucleotide variant
Location: chr19:11105253 (GRCh38)
Gene constraint: LOEUF 1.091 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.81 · 36 PDB
Residue 116: a disulfide bond; the ldl-receptor class a 3 domain; a UniProt-annotated variant site (in fhcl1; does not affect receptor expression at the cell surface; results in reduced ldl binding; results in reduced ldl uptake and internalization)

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.Cys116Arg Pathogenic/Likely pathogenic ★★ same residue
LDLR p.Cys116_Ile122del Likely pathogenic ★★ same residue
LDLR p.Cys116_His117delinsTyr Likely pathogenic ★ same residue
LDLR p.Cys116Ter Likely pathogenic ★ same residue
LDLR p.Cys116Tyr Conflicting classifications of pathogenicity ★ ⚠ same residue
LDLR p.Cys116= Likely benign ★ 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-cys116phe (accessed [today's date]).

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