Is LDLR p.Pro661Ala (c.1981C>G) pathogenic?

LDLR p.Pro661Ala (c.1981C>G) is classified Likely pathogenic in LDLR (ClinVar, Expert panel, 5 submitters; last evaluated 2023-06-23). AlphaMissense: likely benign (0.2617); Absent from gnomAD v4.1; Associated with hypercholesterolemia, familial, 1.

What condition is associated with LDLR p.Pro661Ala (c.1981C>G)?

LDLR p.Pro661Ala (c.1981C>G) is associated with hypercholesterolemia, familial, 1, familial hypercholesterolemia (ClinVar).

How common is LDLR p.Pro661Ala (c.1981C>G) in the general population?

LDLR p.Pro661Ala (c.1981C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about LDLR p.Pro661Ala (c.1981C>G)?

AlphaMissense predicts likely benign (score 0.2617) — an in-silico prediction, not a clinical call.

LDLR p.Pro661Ala

c.1981C>G · rs1182317785 · VCV810849

Likely pathogenic Expert panel

Classification

Likely pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.2617 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hypercholesterolemia, familial, 1

ClinGen expert panel — Familial Hypercholesterolemia VCEP

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

PM2 PS3 PP4

Curation rationale (ClinGen, verbatim)

The NM_000527.5(LDLR):c.1981C>G (p.Pro661Ala) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PS3, PM2 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 23 June 2023. The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD v2.1.1). PS3: Level 1 assays: PMID 31689621 (Gomez et al., 2019): Heterologous cells (CHO-ldlA7), RT qPCR and 125I-LDL assays - results – normal (100%) LDLR expression and 50% uptake and catabolism -> results are below 70% of wild-type, so functional study is consistent with damaging effect. PP4: Variant meets PM2 and is identified in 1 case from Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon (France) with DLCN score ≥ 6, after alternative causes of high cholesterol were excluded.

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

Computational evidence

Protein change
AlphaMissense	0.2617	likely benign ⚠ discordant with ClinVar
REVEL	0.639	indeterminate
SaProt	LLR -10.97	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
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	22.6	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.Pro661Ala
Coding: c.1981C>G
MANE Select: NM_000527
dbSNP: rs1182317785
Type: single nucleotide variant
Location: chr19:11120227 (GRCh38)
Gene constraint: LOEUF 1.091 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.81 · 36 PDB

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.Pro661Leu Uncertain significance ★★★ ⚠ same residue
LDLR p.Pro661Thr Uncertain significance ★★★ ⚠ same residue
LDLR p.Pro661Ser Uncertain significance ★ ⚠ same residue
LDLR p.Pro661fs 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-pro661ala (accessed [today's date]).

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