Is LDLR p.Asp307Glu (c.921T>G) pathogenic?

LDLR p.Asp307Glu (c.921T>G) is classified Pathogenic/Likely pathogenic in LDLR (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-04-01). AlphaMissense: likely pathogenic (0.9786); Absent from gnomAD v4.1; Associated with Dyslipidemia.

What condition is associated with LDLR p.Asp307Glu (c.921T>G)?

LDLR p.Asp307Glu (c.921T>G) is associated with Dyslipidemia, hypercholesterolemia, familial, 1 (ClinVar).

How common is LDLR p.Asp307Glu (c.921T>G) in the general population?

LDLR p.Asp307Glu (c.921T>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about LDLR p.Asp307Glu (c.921T>G)?

AlphaMissense predicts likely pathogenic (score 0.9786) — an in-silico prediction, not a clinical call.

LDLR p.Asp307Glu

c.921T>G · rs879254720 · VCV251527

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9786 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Dyslipidemia

ClinGen expert panel — Familial Hypercholesterolemia VCEP

Uncertain Significance for hypercholesterolemia, familial. Applied ACMG criteria (verbatim):

PM2 PS4_Supporting PP3 PP4

Curation rationale (ClinGen, verbatim)

The NM_000527.5(LDLR):c.921T>G (p.Asp307Glu) variant is classified as VUS for Familial Hypercholesterolemia by applying evidence codes PM2, PP3, and PP4 and PS4_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD v2.1.1). PP3: REVEL = 0.85. PP4: Variant meets PM2 and is identified in at least 1 index case who fulfills SB definite FH after alternative causes of high cholesterol were excluded (PMID: 12436241). PS4_Supporting: Variant meets PM2 and is identified in at least 2 unrelated index cases who fulfill SB definite FH/DLCN>=6 for FH (PMID: 12436241, Lille University SCV000583761.1).

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
AlphaMissense	0.9786	likely pathogenic ✓ concordant with ClinVar · top 10% in LDLR
REVEL	0.85	moderately pathogenic-leaning
SaProt	LLR -11.83	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 -13	GERP -3.7
Regional constraint	o/e 1.00	unconstrained · MANE · 42 kb · p 0.91 · regional, not allelic
Overall
CADD	18.09	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.Asp307Glu
Coding: c.921T>G
MANE Select: NM_000527
dbSNP: rs879254720
Type: single nucleotide variant
Location: chr19:11107495 (GRCh38)
Gene constraint: LOEUF 1.091 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.81 · 36 PDB
Residue 307: the ldl-receptor class a 7 domain; a β-strand; a disulfide bond

Full LDLR gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Dyslipidemia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hypercholesterolemia, familial, 1

Similar variants

LDLR p.Asp307Gly Pathogenic/Likely pathogenic ★★ same residue
LDLR p.Asp307His Likely pathogenic ★★ same residue
LDLR p.Asp307Ala Conflicting classifications of pathogenicity ★ ⚠ same residue
LDLR p.Asp307Asn Conflicting classifications of pathogenicity ★ ⚠ same residue
LDLR p.Asp307Tyr Uncertain significance ★ ⚠ same residue
LDLR p.Asp307fs 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-asp307glu (accessed [today's date]).

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