LDLR p.Val653Ala
c.1958_1959delinsCC · rs2077526251 · VCV1008168
ClinGen expert panel — Familial Hypercholesterolemia VCEP
Uncertain Significance for hypercholesterolemia, familial. Applied ACMG criteria (verbatim):
PM2
Curation rationale (ClinGen, verbatim)
The NM_000527.5 (LDLR):c.1958_1959delinsCC (p.Val653Ala) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence code PM2 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 23 February 2024. The supporting evidence is as follows: PM2: The multi-nucleotide variant 19-1230880-TT-CC is observed once in at least 251454 total alleles from gnomAD (gnomAD v2.1.1). PopMax MAF for 19-11230880-T-C (NM_000527.5 (LDLR):c.1958T>C (p.Val653Ala) (CA305302665) is 0.00009921 (1/10080 alleles) in Ashkenazi Jewish population (gnomAD v2.1.1), whereas 19-11230881-T-C (NM_000527.5 (LDLR):c.1959T>C (p.Val653=) (ClinVar ID 252131) is a common variant with Grpmax FAF of 0.5225 (gnomAD v2.1.1).
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| Splicing | ||
| SpliceAI | — | not assessed · substitutions only |
|---|---|---|
| Constraint at this position | ||
| Conservation | phyloP 7.7 | GERP 2.2, phastCons 1 |
| Regional constraint | o/e 1.00 | unconstrained · MANE · 42 kb · p 0.91 · regional, not allelic |
Population frequency
No gnomAD frequency available for this variant. This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.
Variant & gene context
- Gene
- LDLR
- Protein
- p.Val653Ala
- Coding
- c.1958_1959delinsCC
- MANE Select
- NM_000527
- dbSNP
- rs2077526251
- Type
- Indel
- Location
- chr19:11120204 (GRCh38)
- Gene constraint
- LOEUF 1.091 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
- Structure
- AlphaFold pLDDT 75.81 · 36 PDB
- Residue 653
- a β-strand
Similar variants
- LDLR p.Val653Gly Uncertain significance ★★★ ⚠ same residue
- LDLR p.Val653Ile Uncertain significance ★★★ ⚠ same residue
- LDLR p.Val653Phe Uncertain significance ★★★ ⚠ same residue
- LDLR p.Val653= Benign/Likely benign ★★ same residue
- LDLR c.1359-31_1359-23delinsCGGCT Uncertain significance ★★★ same condition
- LDLR p.Arg257His Uncertain significance ★★★ same condition
- LDLR p.Arg744Gln Uncertain significance ★★★ same condition
- LDLR p.Asp224_Lys225delinsPhe Uncertain significance ★★★ 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-val653ala (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown