Is LDLR p.Trp577Ter (c.1731G>A) pathogenic?

LDLR p.Trp577Ter (c.1731G>A) is classified Pathogenic in LDLR (ClinVar, Multiple submitters, 7 submitters; last evaluated 2025-12-18). Very rare (popmax 0.0011%, sas); Associated with familial hypercholesterolemia.

What condition is associated with LDLR p.Trp577Ter (c.1731G>A)?

LDLR p.Trp577Ter (c.1731G>A) is associated with familial hypercholesterolemia, hypercholesterolemia, familial, 1 (ClinVar).

How common is LDLR p.Trp577Ter (c.1731G>A) in the general population?

LDLR p.Trp577Ter (c.1731G>A) is very rare (popmax 0.0011%, sas) (gnomAD).

LDLR p.Trp577Ter

c.1731G>A · rs875989928 · VCV226370

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Conditions

familial hypercholesterolemia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	predicted	premature termination codon in exon 12 of 18
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.5, phastCons 1
Overall
CADD	50.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,072 alleles

Overall 6.2e-05% 1/1,613,822 alleles · very rare exomes 0/1,461,774 · genomes 1/152,048 · 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.Trp577Ter
Coding: c.1731G>A
MANE Select: NM_000527
dbSNP: rs875989928
Type: single nucleotide variant
Location: chr19:11116884 (GRCh38)
Gene constraint: LOEUF 1.091 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.81 · 36 PDB
Residue 577: a UniProt-annotated variant site (in fhcl1; pathogenic; results in loss of receptor expression at the cell surface); a UniProt-annotated variant site (in fhcl1; uncertain significance); a β-strand

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.Trp577Gly Pathogenic ★★★ same residue
LDLR p.Trp577Arg Pathogenic ★★ same residue
LDLR p.Trp577Ser Pathogenic/Likely pathogenic ★★ same residue
LDLR p.Trp577Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
LDLR p.Trp577_Asp579del Likely pathogenic ★ same residue
LDLR p.Trp577fs Pathogenic ★ 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-trp577ter (accessed [today's date]).

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