Is LDLR p.Arg595Trp (c.1783C>T) pathogenic?

LDLR p.Arg595Trp (c.1783C>T) is classified Pathogenic in LDLR (ClinVar, Expert panel, 32 submitters; last evaluated 2021-06-09). AlphaMissense: ambiguous (0.3756); Very rare (popmax 0.00446%, eas); Associated with hypercholesterolemia, familial, 1.

What condition is associated with LDLR p.Arg595Trp (c.1783C>T)?

LDLR p.Arg595Trp (c.1783C>T) is associated with hypercholesterolemia, familial, 1, familial hypercholesterolemia (ClinVar).

How common is LDLR p.Arg595Trp (c.1783C>T) in the general population?

LDLR p.Arg595Trp (c.1783C>T) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about LDLR p.Arg595Trp (c.1783C>T)?

AlphaMissense predicts ambiguous (score 0.3756) — an in-silico prediction, not a clinical call.

LDLR p.Arg595Trp

c.1783C>T · rs373371572 · VCV161290

Pathogenic Expert panel

Classification

Pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 32 submitters

AlphaMissense

ambiguous

0.3756 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

hypercholesterolemia, familial, 1

ClinGen expert panel — Familial Hypercholesterolemia VCEP

Pathogenic for hypercholesterolemia, familial. Applied ACMG criteria (verbatim):

PM2 PP1_Strong PS4 PP3 PP4

Curation rationale (ClinGen, verbatim)

NM_000527.5(LDLR):c.1783C>T (p.Arg595Trp) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PS4, PP1_Strong, PM2, PP3 and PP4) 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: PS4 - Variant meets PM2. Variant identified in 12 index cases. PP1_strong - 10 informative meioses identified by Laboratory of Genetics and Molecular Cardiology. PM2 - PopMax MAF = 0.00001548 (0.0015%) in European non-Finnish (gnomAD v2.1.1). PP3 - REVEL: 0,89. PP4 - Variant meets PM2. Variant identified in 12 index cases fulfilling validated clinical criteria for FH (6 cases with Simon-Broome or DLCN criteria from Ambry Genetics; 2 cases with Simon-Broome from Color laboratory; 3 cases with Simon-Broome criteria from Laboratory of Genetics and Molecular Cardiology; 1 case with Simon-Broome criteria from GeneDx).

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
AlphaMissense	0.3756	ambiguous
REVEL	0.89	moderately pathogenic-leaning
SaProt	LLR -12.75	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 1.4	GERP 0.26, phastCons 0.97
Regional constraint	o/e 1.00	unconstrained · MANE · 42 kb · p 0.91 · regional, not allelic
Overall
CADD	25.9	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00446% East Asian · 2/44,884 alleles

Filtering AF 0.000875% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000605%

Overall 0.00161% 26/1,613,914 alleles · very rare exomes 22/1,461,856 · genomes 4/152,058 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0048%	20,827
East Asiangrpmax	0.00446%	22,442
South Asian	0.00329%	30,361
African / African-American	0.00267%	37,447
Admixed American	0.00167%	59,962
European (non-Finnish)	0.00127%	78,666

Remaining individuals 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.Arg595Trp
Coding: c.1783C>T
MANE Select: NM_000527
dbSNP: rs373371572
Type: single nucleotide variant
Location: chr19:11116936 (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)

Full LDLR gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hypercholesterolemia, familial, 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: familial hypercholesterolemia

Similar variants

LDLR p.Arg595Gln Pathogenic ★★★ ⚠ same residue
LDLR p.Arg595Leu Likely 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-arg595trp (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown