LDLR p.Ala606Ser
c.1816G>T · rs72658865 · VCV161264
ClinGen expert panel — Familial Hypercholesterolemia VCEP
Uncertain Significance for hypercholesterolemia, familial. Applied ACMG criteria (verbatim):
PP1
Curation rationale (ClinGen, verbatim)
The NM_000527.5(LDLR):c.1816G>T (p.Ala606Ser) variant is classified as variant of Uncertain significance for Familial Hypercholesterolemia by applying evidence codes (PP1) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PP1 - 2 informative meioses identified by Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge.
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.0883 | likely benign |
|---|---|---|
| REVEL | 0.6 | indeterminate |
| SaProt | LLR -5.96 | tolerated |
| ⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
| Constraint at this position | ||
| Conservation | phyloP 6.4 | GERP 2.3, phastCons 1 |
| Regional constraint | o/e 1.00 | unconstrained · MANE · 42 kb · p 0.91 · regional, not allelic |
| Overall | ||
| CADD | 18.69 | PHRED · no single calibrated threshold — expert panels disagree |
ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification
AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.
Population frequency
| Ancestry group | Frequency | 1 in |
|---|---|---|
| European (non-Finnish)grpmax | 0.0355% | 2,816 |
| Remaining individualsnot grpmax-eligible | 0.008% | 12,500 |
| African / African-American | 0.00533% | 18,754 |
| Admixed American | 0.00167% | 59,976 |
| Finnishnot grpmax-eligible | 0.00156% | 64,002 |
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.Ala606Ser
- Coding
- c.1816G>T
- MANE Select
- NM_000527
- dbSNP
- rs72658865
- Type
- single nucleotide variant
- Location
- chr19:11116969 (GRCh38)
- Gene constraint
- LOEUF 1.091 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
- Structure
- AlphaFold pLDDT 75.81 · 36 PDB
- Residue 606
- a β-strand
Similar variants
- LDLR p.Ala606Asp Uncertain significance ★★★ ⚠ same residue
- LDLR p.Ala606Thr Uncertain significance ★★★ ⚠ same residue
- LDLR p.Ala606= Likely benign ★ same residue
- LDLR p.Ala606fs Pathogenic ★★ 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
- LDLR c.1705+2T>C 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-ala606ser (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown