LDLR p.Arg595Gln
c.1784G>A · rs201102492 · VCV183126
ClinGen expert panel — Familial Hypercholesterolemia VCEP
Pathogenic for hypercholesterolemia, familial. Applied ACMG criteria (verbatim):
PM2 PS3_Supporting PS4 PP3 PP4 PM3 PM5
Curation rationale (ClinGen, verbatim)
The NM_000527.5(LDLR):c.1784G>A (p.Arg595Gln) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3, PM5, PS3_supporting, PS4, PP4, PM3) 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 - PopMax MAF = 0.0002389 (0.02389%) in European (Finnish) exomes+genomes (gnomAD v2.1.1), since this is a founder effect variant in Finnish population (PMID: 11585102) we can consider PopMax MAF = 0.00005012 (0.005012%) in East Asian exomes+genomes (gnomAD v2.1.1), so PM2 is Met. PP3 - REVEL = 0.956. It is above 0.75, so PP3 is Met. PM5 - 2 other missense variants in the same codon: - NM_000527.5(LDLR):c.1783C>T (p.Arg595Trp) (ClinVar ID: 161290) - Pathogenic by these guidelines - NM_000527.5(LDLR):c.1784G>T (p.Arg595Leu) (ClinVar ID: 252029) - Likely pathogenic by these guidelines There is 1 variant in the same codon classified as Pathogenic by these guidelines, so PM5 is Met. PS3_supporting - Level 3 assay: PMID 11585102: Heterozygous patient cells, 125I-LDL assays - result - 70% LDL-LDLR binding, 54-49% LDL-LDLR uptake and degradation. ---- functional study is consistent with damaging effect, so PS3_Supporting is Met. PS4 - Variant meets PM2 and is identified in 11 unrelated index cases: 1 index case with Simon Broome definite criteria from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation), 4 index cases with DLCN criteria for FH (LDL > 95th percentile and presence of tendon xanthomas) from Finland (PMID: 11585102), 1 index case with FH criteria suggested by the Japan Atherosclerosis Society (TC > 260 mg/dL with tendon xanthomas OR TC > 260 mg/dL and TC > 260 mg/dL with tendon xanthomas in first or second degree relatives) from Japan ( PMID: 18718593), 1 index case with DLCN criteria for FH (score=8) from Sweden (PMID: 29974534), 1 index case with DLCN criteria for FH (score>=6) from Argentina (PMID: 30270055), 2 index cases with DLCN criteria for FH (score>=6) from Russia (PMID: 33418990), 1 index case with homozygous FH phenotype (LDL = 16 mmol/L) from The Netherlands (PMID: 24585268), so PS4 is Met. PP4 - Variant meets PM2 and is identified in 11 unrelated index cases as described before, so PP4 is Met. PM3 - Variant meets PM2 and is identified in an index case with homozygous FH phenotype (LDL = 16 mmol/L) and LDLR variant c.(1705+1_1706-1)_(*2514_?)del (described as 16kb deletion exon 12-18) (PMID: 24585268), classified as Pathogenic by these guidelines, in trans, so PM3 is Met.
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.1949 | likely benign ⚠ discordant with ClinVar |
|---|---|---|
| REVEL | 0.956 | strongly pathogenic-leaning |
| SaProt | LLR -10.79 | damaging |
| ⇒ REVEL and SaProt call this damaging; AlphaMissense does not. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
| Constraint at this position | ||
| Conservation | phyloP 12 | GERP 2.5, phastCons 1 |
| Regional constraint | o/e 1.00 | unconstrained · MANE · 42 kb · p 0.91 · regional, not allelic |
| Overall | ||
| CADD | 32.0 | PHRED · no single calibrated threshold — expert panels disagree |
AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.
Population frequency
| Ancestry group | Frequency | 1 in |
|---|---|---|
| Finnishnot grpmax-eligible | 0.025% | 4,002 |
| East Asiangrpmax | 0.00446% | 22,436 |
| Remaining individualsnot grpmax-eligible | 0.0016% | 62,504 |
| South Asian | 0.0011% | 91,086 |
| European (non-Finnish) | 0.000508% | 196,665 |
Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.
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.Arg595Gln
- Coding
- c.1784G>A
- MANE Select
- NM_000527
- dbSNP
- rs201102492
- Type
- single nucleotide variant
- Location
- chr19:11116937 (GRCh38)
- Gene constraint
- LOEUF 1.091 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
- Structure
- AlphaFold pLDDT 75.81 · 36 PDB
- Residue 595
- a UniProt-annotated variant site (in fhcl1; pathogenic)
Similar variants
- LDLR p.Arg595Leu Likely pathogenic ★★★ same residue
- LDLR p.Arg595Trp Pathogenic ★★★ same residue
- LDLR p.Arg595= Likely benign ★ same residue
- LDLR p.Arg595fs 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-arg595gln (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown