Is LDLR p.Ala627Asp (c.1880C>A) pathogenic?

LDLR p.Ala627Asp (c.1880C>A) is classified Pathogenic/Likely pathogenic in LDLR (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-02-16). AlphaMissense: likely pathogenic (0.7393); Absent from gnomAD v4.1; Associated with familial hypercholesterolemia.

What condition is associated with LDLR p.Ala627Asp (c.1880C>A)?

LDLR p.Ala627Asp (c.1880C>A) is associated with familial hypercholesterolemia, hypercholesterolemia, familial, 1 (ClinVar).

How common is LDLR p.Ala627Asp (c.1880C>A) in the general population?

LDLR p.Ala627Asp (c.1880C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about LDLR p.Ala627Asp (c.1880C>A)?

AlphaMissense predicts likely pathogenic (score 0.7393) — an in-silico prediction, not a clinical call.

LDLR p.Ala627Asp

c.1880C>A · rs875989934 · VCV226377

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.7393 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

familial hypercholesterolemia

Computational evidence

Protein change
AlphaMissense	0.7393	likely pathogenic ✓ concordant with ClinVar
REVEL	0.898	moderately pathogenic-leaning
SaProt	LLR -13.87	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>T here scores Δ0.25 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.5	GERP 2.2, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 42 kb · p 0.91 · regional, not allelic
Overall
CADD	27.7	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

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.Ala627Asp
Coding: c.1880C>A
MANE Select: NM_000527
dbSNP: rs875989934
Type: single nucleotide variant
Location: chr19:11120126 (GRCh38)
Gene constraint: LOEUF 1.091 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.81 · 36 PDB
Residue 627: a β-strand

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

Disease context

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

Also linked: hypercholesterolemia, familial, 1

Similar variants

LDLR p.Ala627Thr Pathogenic/Likely pathogenic ★★ ⚠ same residue
LDLR p.Ala627Val Likely pathogenic ★★ same residue
LDLR p.Ala627= Likely benign ★★ same residue
LDLR p.Ala627Gly Uncertain significance ★ ⚠ same residue
LDLR p.Ala627fs Pathogenic/Likely pathogenic ★★ same residue
LDLR p.Ala627Pro Uncertain significance ★ ⚠ same residue
LDLR c.1186+5G>A Likely pathogenic ★★★ same condition
LDLR c.1359-1G>A 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-ala627asp (accessed [today's date]).

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