Is LDLR p.Trp6fs (c.16_17insTTCCT) pathogenic?

LDLR p.Trp6fs (c.1617insTTCCT) is classified Likely pathogenic in LDLR (ClinVar, Single submitter, 1 submitter). Very rare (popmax 0.0011%, sas); Associated with hypercholesterolemia, familial, 1.

What condition is associated with LDLR p.Trp6fs (c.16_17insTTCCT)?

LDLR p.Trp6fs (c.16_17insTTCCT) is associated with hypercholesterolemia, familial, 1 (ClinVar).

How common is LDLR p.Trp6fs (c.16_17insTTCCT) in the general population?

LDLR p.Trp6fs (c.16_17insTTCCT) is very rare (popmax 0.0011%, sas) (gnomAD).

LDLR p.Trp6fs

c.16_17insTTCCT · rs774615547 · VCV369864

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Conditions

hypercholesterolemia, familial, 1

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 1 of 18
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.088	GERP -2.1, phastCons 0.029

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,010 alleles

Overall 6.2e-05% 1/1,612,480 alleles · very rare exomes 1/1,460,184 · genomes 0/152,296 · 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.Trp6fs
Coding: c.16_17insTTCCT
MANE Select: NM_000527
dbSNP: rs774615547
Type: Insertion
Location: chr19:11089562 (GRCh38)
Gene constraint: LOEUF 1.091 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.81 · 36 PDB

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 c.1705+2_1705+3insC Pathogenic/Likely pathogenic ★★ same condition
LDLR p.Ala437delinsValAlaLeuAspThrTer Pathogenic ★★ same condition
LDLR p.Arg778fs Pathogenic ★★ same condition
LDLR p.Gln125delinsHisTer Pathogenic ★★ same condition
LDLR p.Phe807fs Pathogenic ★★ same condition
LDLR p.Ser194fs Pathogenic ★★ same condition
LDLR p.Trp6Ter Pathogenic ★★ same residue
LDLR c.680_681ins(21 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-trp6fs (accessed [today's date]).

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