Is LDLR p.Gly343Asp (c.1028G>A) pathogenic?

LDLR p.Gly343Asp (c.1028G>A) is classified Likely pathogenic in LDLR (ClinVar, Expert panel, 5 submitters; last evaluated 2023-01-27). AlphaMissense: likely pathogenic (0.7986); Very rare (popmax 8.47e-05%, nfe); Associated with hypercholesterolemia, familial, 1.

What condition is associated with LDLR p.Gly343Asp (c.1028G>A)?

LDLR p.Gly343Asp (c.1028G>A) is associated with hypercholesterolemia, familial, 1, familial hypercholesterolemia (ClinVar).

How common is LDLR p.Gly343Asp (c.1028G>A) in the general population?

LDLR p.Gly343Asp (c.1028G>A) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about LDLR p.Gly343Asp (c.1028G>A)?

AlphaMissense predicts likely pathogenic (score 0.7986) — an in-silico prediction, not a clinical call.

LDLR p.Gly343Asp

c.1028G>A · rs879254760 · VCV251606

Likely pathogenic Expert panel

Classification

Likely pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.7986 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hypercholesterolemia, familial, 1

ClinGen expert panel — Familial Hypercholesterolemia VCEP

Likely Pathogenic for hypercholesterolemia, familial. Applied ACMG criteria (verbatim):

PM2 PM5_Strong PP3 PP4

Curation rationale (ClinGen, verbatim)

The NM_000527.5 (LDLR):c.1028G>A (p.Gly343Asp) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3, PP4, PM5_Strong) 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=0.959, it is above 0.75. PP4: Variant meets PM2 and is identified in 1 index case who fulfil DLCN criteria for definite FH after alternative causes of high cholesterol were excluded, reported in ClinVar (SCV000583778.1) from U4M - Lille University & CHRU Lille, Universite de Lille - CHRU de Lille, France. PM5_Strong: Three other variants at the same codon: NM_000527.5(LDLR):c.1028G>T (p.Gly343Val)(ClinVarID 440618) classified as Likely Pathogenic, NM_000527.5(LDLR):c.1027G>A (p.Gly343Ser)(ClinVarID 183106) is classified as Pathogenic, NM_000527.5(LDLR):c.1027G>T (p.Gly343Cys)(ClinVarID 251605) is classified as Pathogenic by these guidelines, therefore PM5_Strong is met. PS4 not met: Variant meets PM2 and is reported in 1 index case and family fulfil FH criteria, reported from U4M - Lille University & CHRU Lille, Universite de Lille - CHRU de Lille, France. PS3 not met: Functional data is not available.

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

Computational evidence

Protein change
AlphaMissense	0.7986	likely pathogenic ✓ concordant with ClinVar
REVEL	0.959	strongly pathogenic-leaning
SaProt	LLR -12.54	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 2.4, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 42 kb · p 0.91 · regional, not allelic
Overall
CADD	26.6	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

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,179,994 alleles

Overall 6.2e-05% 1/1,613,788 alleles · very rare exomes 1/1,461,478 · genomes 0/152,310 · 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.Gly343Asp
Coding: c.1028G>A
MANE Select: NM_000527
dbSNP: rs879254760
Type: single nucleotide variant
Location: chr19:11110739 (GRCh38)
Gene constraint: LOEUF 1.091 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.81 · 36 PDB
Residue 343: the egf-like 1 domain; a UniProt-annotated variant site (in fhcl1; pathogenic; picardie); a β-strand

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

Also linked: familial hypercholesterolemia

Similar variants

LDLR p.Gly343Cys Pathogenic ★★★ same residue
LDLR p.Gly343Ser Pathogenic ★★★ same residue
LDLR p.Gly343Val Likely pathogenic ★★★ same residue
LDLR p.Gly343Ala Likely pathogenic ★ same residue
LDLR p.Gly343= Likely benign ★ same residue
LDLR c.1186+5G>A Likely pathogenic ★★★ same condition
LDLR c.1359-1G>A Pathogenic ★★★ same condition
LDLR c.1359-5C>G 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-gly343asp (accessed [today's date]).

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