LDLR p.Ser244Cys
c.731C>G · rs1208667598 · VCV440599
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.731C>G (p.Ser244Cys) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence code PM2 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: No exome data available for this variant in gnomAD v2.1.1. Genome and exome data were available for the neighboring variant, 19-11217264-G-A(GRCh37). The c.731C>G (p.Ser244Cys) variant was present in 1/15432 European (non-Finnish) genomes. The 19-11217264-G-A(GRCh37) variant was tested in 113760 alles from European (non-Finnish) exomes. Final adjusted allele frequency: 1/( 15432+ 113760) = 0.0007740417%.
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.5965 | likely pathogenic |
|---|---|---|
| REVEL | 0.513 | indeterminate |
| SaProt | LLR -12.01 | damaging |
| ⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
| Constraint at this position | ||
| Conservation | phyloP -2 | GERP -3.7 |
| Regional constraint | o/e 1.00 | unconstrained · MANE · 42 kb · p 0.91 · regional, not allelic |
| Overall | ||
| CADD | 15.99 | PHRED · no single calibrated threshold — expert panels disagree |
ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification
AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.
Population frequency
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.Ser244Cys
- Coding
- c.731C>G
- MANE Select
- NM_000527
- dbSNP
- rs1208667598
- Type
- single nucleotide variant
- Location
- chr19:11106601 (GRCh38)
- Gene constraint
- LOEUF 1.091 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
- Structure
- AlphaFold pLDDT 75.81 · 36 PDB
- Residue 244
- the ldl-receptor class a 6 domain; a turn
Similar variants
- 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
- LDLR c.190+4A>T Likely pathogenic ★★★ same condition
- LDLR c.2140+1G>A Pathogenic ★★★ same condition
- LDLR c.2389+2T>G Pathogenic ★★★ same condition
- LDLR c.313+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-ser244cys (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown