Is LDLR p.Asp362Ala (c.1085A>C) pathogenic?

LDLR p.Asp362Ala (c.1085A>C) is classified Uncertain significance in LDLR (ClinVar, Expert panel, 18 submitters; last evaluated 2023-04-28). AlphaMissense: likely benign (0.1092); Ultra-rare (popmax 0.019%, nfe); Associated with hypercholesterolemia, familial, 1.

What condition is associated with LDLR p.Asp362Ala (c.1085A>C)?

LDLR p.Asp362Ala (c.1085A>C) is associated with hypercholesterolemia, familial, 1, familial hypercholesterolemia (ClinVar).

How common is LDLR p.Asp362Ala (c.1085A>C) in the general population?

LDLR p.Asp362Ala (c.1085A>C) is ultra-rare (popmax 0.019%, nfe) (gnomAD).

What do computational predictors say about LDLR p.Asp362Ala (c.1085A>C)?

AlphaMissense predicts likely benign (score 0.1092) — an in-silico prediction, not a clinical call.

LDLR p.Asp362Ala

c.1085A>C · rs138315511 · VCV36452

Uncertain significance Expert panel

Classification

Uncertain significance

ClinVar

Review

Expert panel ★★★☆

ClinVar · 18 submitters

AlphaMissense

likely benign

0.1092 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.019%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hypercholesterolemia, familial, 1

ClinGen expert panel — Familial Hypercholesterolemia VCEP

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

PM2 PS4_Moderate PP4

Curation rationale (ClinGen, verbatim)

The NM_000527.5(LDLR):c.1085A>C (p.Asp362Ala) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP4 and PS4_Moderate) 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 = 0.0001782 (0.01782%) in European (non-Finnish) exomes+genomes (gnomAD v2.1.1). PS4_Moderate - Variant meets PM2 and is identified in 8 unrelated index cases (5 cases with Simon-Broome criteria of definite/possible FH published in PMID: 16542394, Denmark; at least 1 case with DLCN≥6 published in PMID: 11810272, Netherlands; 1 case with DLCN criteria ≥6 from Robarts Research Institute, Canada; 1 case with Simon-Broome criteria of possible FH from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation), Czechia. PP4 - Variant meets PM2 and is identified in at least one case who fufills clinical criteria for FH (see PS4 for details), after alternative causes of high cholesterol were excluded.

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

Computational evidence

Protein change
AlphaMissense	0.1092	likely benign
REVEL	0.7	pathogenic-leaning
SaProt	LLR -4.73	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4	GERP -1.6, phastCons 0.11
Regional constraint	o/e 1.00	unconstrained · MANE · 42 kb · p 0.91 · regional, not allelic
Overall
CADD	22.3	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 0.019% European (non-Finnish) · 224/1,179,864 alleles

Filtering AF 0.0169% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0162%

Overall 0.0149% 240/1,613,644 alleles · ultra-rare exomes 229/1,461,506 · genomes 11/152,138 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.019%	5,267
Remaining individualsnot grpmax-eligible	0.016%	6,247
Finnishnot grpmax-eligible	0.00626%	15,968
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,606
East Asian	0.00223%	44,874

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.Asp362Ala
Coding: c.1085A>C
MANE Select: NM_000527
dbSNP: rs138315511
Type: single nucleotide variant
Location: chr19:11111538 (GRCh38)
Gene constraint: LOEUF 1.091 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.81 · 36 PDB
Residue 362: the egf-like 2; calcium-binding domain

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.Asp362Asn Uncertain significance ★ ⚠ same residue
LDLR p.Asp362Val Uncertain significance ★ ⚠ same residue
LDLR p.Asp362= Likely benign ★ same residue
LDLR p.Asp362fs 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-asp362ala (accessed [today's date]).

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