Is LDLR p.Val66fs (c.196_197del) pathogenic?

LDLR p.Val66fs (c.196197del) is classified Pathogenic in LDLR (ClinVar, Multiple submitters, 3 submitters; last evaluated 2018-03-27). Very rare (popmax 0.00017%, nfe); Associated with familial hypercholesterolemia.

What condition is associated with LDLR p.Val66fs (c.196_197del)?

LDLR p.Val66fs (c.196_197del) is associated with familial hypercholesterolemia, hypercholesterolemia, familial, 1 (ClinVar).

How common is LDLR p.Val66fs (c.196_197del) in the general population?

LDLR p.Val66fs (c.196_197del) is very rare (popmax 0.00017%, nfe) (gnomAD).

LDLR p.Val66fs

c.196_197del · rs875989889 · VCV226307

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Conditions

familial hypercholesterolemia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	predicted	premature termination codon in exon 3 of 18
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 4.7	GERP -1.1, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00017% European (non-Finnish) · 2/1,179,632 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,613,566 alleles · very rare exomes 2/1,461,276 · genomes 0/152,290 · joint denominator

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.Val66fs
Coding: c.196_197del
MANE Select: NM_000527
dbSNP: rs875989889
Type: Deletion
Location: chr19:11102668 (GRCh38)
Gene constraint: LOEUF 1.091 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.81 · 36 PDB
Residue 66: a β-strand; the ldl-receptor class a 2 domain

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.Val66Ala Uncertain significance ★ ⚠ same residue
LDLR p.Val66= Likely benign ★ same residue
LDLR p.Ala612fs Likely pathogenic ★★★ same condition
LDLR p.Lys816fs Likely pathogenic ★★★ same condition
LDLR p.Tyr400_Phe402del Likely pathogenic ★★★ same condition
LDLR p.Val800fs Likely pathogenic ★★★ same condition
LDLR p.Phe86_Arg88del Uncertain significance ★★★ same condition
LDLR c.1056_1060+3del Pathogenic/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-val66fs (accessed [today's date]).

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