Is LDLR p.Asp57Ala (c.170A>C) pathogenic?

LDLR p.Asp57Ala (c.170A>C) is classified Uncertain significance in LDLR (ClinVar, Expert panel, 2 submitters; last evaluated 2022-08-29). AlphaMissense: likely pathogenic (0.9958); Absent from gnomAD v4.1; Associated with hypercholesterolemia, familial, 1.

What condition is associated with LDLR p.Asp57Ala (c.170A>C)?

LDLR p.Asp57Ala (c.170A>C) is associated with hypercholesterolemia, familial, 1 (ClinVar).

How common is LDLR p.Asp57Ala (c.170A>C) in the general population?

LDLR p.Asp57Ala (c.170A>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about LDLR p.Asp57Ala (c.170A>C)?

AlphaMissense predicts likely pathogenic (score 0.9958) — an in-silico prediction, not a clinical call.

LDLR p.Asp57Ala

c.170A>C · rs1555802310 · VCV523722

Uncertain significance Expert panel

Classification

Uncertain significance

ClinVar

Review

Expert panel ★★★☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9958 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hypercholesterolemia, familial, 1

ClinGen expert panel — Familial Hypercholesterolemia VCEP

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

PM2 PP3

Curation rationale (ClinGen, verbatim)

The NM_000527.5(LDLR):c.170A>C (p.Asp57Ala) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PM2 and PP3 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= 0.959. It is above 0.75, so PP3 is met.

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

Computational evidence

Protein change
AlphaMissense	0.9958	likely pathogenic · top 3% in LDLR
REVEL	0.959	strongly pathogenic-leaning
SaProt	LLR -14.04	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>G here scores Δ1.00 · evaluated, not missing
Constraint at this position
Conservation	phyloP 11	GERP 2.4, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 42 kb · p 0.91 · regional, not allelic
Overall
CADD	26.2	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

gnomAD v4.1 · exomes + genomes

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.Asp57Ala
Coding: c.170A>C
MANE Select: NM_000527
dbSNP: rs1555802310
Type: single nucleotide variant
Location: chr19:11100325 (GRCh38)
Gene constraint: LOEUF 1.091 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.81 · 36 PDB
Residue 57: an α-helix; a disulfide bond; the ldl-receptor class a 1 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

Similar variants

LDLR p.Asp57Asn Uncertain significance ★★★ ⚠ same residue
LDLR p.Asp57del Conflicting classifications of pathogenicity ★ same residue
LDLR p.Asp57= Likely benign ★★ same residue
LDLR p.Asp57Gly Uncertain significance ★ ⚠ same residue
LDLR p.Asp57His Uncertain significance ★ ⚠ 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

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-asp57ala (accessed [today's date]).

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