LDLR p.Ser326Pro
c.976T>C · rs2077361498 · VCV998053
ClinGen expert panel — Familial Hypercholesterolemia VCEP
Uncertain Significance for hypercholesterolemia, familial. Applied ACMG criteria (verbatim):
PM2 PP3 PM5
Curation rationale (ClinGen, verbatim)
The NM_000527.5(LDLR):c.976T>C (p.Ser326Pro) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PM2, PP3, PM5 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), so PM2 is Met. PP3 - REVEL = 0.918. It is above 0.75, so PP3 is Met. PM5 - 2 missense variants in the same codon: - NM_000527.5(LDLR):c.977C>T (p.Ser326Phe) (ClinVar ID: 251582) - Likely pathogenic by these guidelines - NM_000527.5(LDLR):c.977C>G (p.Ser326Cys) (ClinVar ID: 251581) - Pathogenic by these guidelines There is 1 variant in the same codon classified as Pathogenic by these guidelines, so PM5 is Met.
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.456 | ambiguous |
|---|---|---|
| REVEL | 0.918 | moderately pathogenic-leaning |
| SaProt | LLR -15.55 | damaging |
| ⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
| Constraint at this position | ||
| Conservation | phyloP 6.1 | GERP 2.4, phastCons 1 |
| Regional constraint | o/e 1.00 | unconstrained · MANE · 42 kb · p 0.91 · regional, not allelic |
| Overall | ||
| CADD | 25.0 | 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.Ser326Pro
- Coding
- c.976T>C
- MANE Select
- NM_000527
- dbSNP
- rs2077361498
- Type
- single nucleotide variant
- Location
- chr19:11110687 (GRCh38)
- Gene constraint
- LOEUF 1.091 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
- Structure
- AlphaFold pLDDT 75.81 · 36 PDB
- Residue 326
- the egf-like 1 domain; a UniProt-annotated variant site (in fhcl1; pathogenic); a β-strand; a disulfide bond
Similar variants
- LDLR p.Ser326Cys Pathogenic ★★★ same residue
- LDLR p.Ser326Phe Likely pathogenic ★★★ same residue
- LDLR p.Ser326= Likely benign ★★ same residue
- LDLR p.Ser326_Cys329del Pathogenic/Likely 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-ser326pro (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown