LDLR p.Gly343Val
c.1028G>T · rs879254760 · VCV440618
ClinGen expert panel — Familial Hypercholesterolemia VCEP
Likely Pathogenic for hypercholesterolemia, familial. Applied ACMG criteria (verbatim):
PM2 PM5_Strong PP3
Curation rationale (ClinGen, verbatim)
The NM_000527.5 (LDLR):c.1028G>T (p.Gly343Val) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3, 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=0.983, it is above 0.75. PM5_Strong: Three other variants at the same codon: NM_000527.5(LDLR):c.1028G>A (p.Gly343Asp)(ClinVarID 251606) is classified as Likely Pathogenic, NM_000527.5(LDLR):c.1027G>T (p.Gly343Cys)(ClinVarID 251605) is classified as Pathogenic, NM_000527.5(LDLR):c.1027G>A (p.Gly343Ser)(ClinVarID 183106) is classified as Pathogenic by these guidelines, therefore PM5_Strong is met. PP4, PS4 not met: Variant meets PM2, and is reported in 1 index case, but the FH diagnosis and clinical information for the patient is not clear, reported by Miyake et al, 2009, National Cardiovascular Center Research Institute, Osaka, Japan, PMID18718593. PS3 not met: Functional data is not available.
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.9258 | likely pathogenic ✓ concordant with ClinVar |
|---|---|---|
| REVEL | 0.983 | strongly pathogenic-leaning |
| SaProt | LLR -16.50 | damaging |
| ⇒ AlphaMissense, REVEL and SaProt all call this damaging. | ||
| Splicing | ||
| SpliceAI | <0.2 | no splice effect predicted · four deltas, not one · how we know |
| 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 | 27.1 | PHRED · no single calibrated threshold — expert panels disagree |
AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.
Population frequency
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.Gly343Val
- Coding
- c.1028G>T
- 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
Similar variants
- LDLR p.Gly343Asp Likely pathogenic ★★★ same residue
- LDLR p.Gly343Cys Pathogenic ★★★ same residue
- LDLR p.Gly343Ser 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-gly343val (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown