Is LDLR p.Val653Ile (c.1957G>A) pathogenic?

LDLR p.Val653Ile (c.1957G>A) is classified Uncertain significance in LDLR (ClinVar, Expert panel, 4 submitters; last evaluated 2024-02-23). AlphaMissense: likely benign (0.0904); Very rare (popmax 0.00167%, amr); Associated with hypercholesterolemia, familial, 1.

What condition is associated with LDLR p.Val653Ile (c.1957G>A)?

LDLR p.Val653Ile (c.1957G>A) is associated with hypercholesterolemia, familial, 1, familial hypercholesterolemia (ClinVar).

How common is LDLR p.Val653Ile (c.1957G>A) in the general population?

LDLR p.Val653Ile (c.1957G>A) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about LDLR p.Val653Ile (c.1957G>A)?

AlphaMissense predicts likely benign (score 0.0904) — an in-silico prediction, not a clinical call.

LDLR p.Val653Ile

c.1957G>A · rs879255085 · VCV628891

Uncertain significance Expert panel

Classification

Uncertain significance

ClinVar

Review

Expert panel ★★★☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0904 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

hypercholesterolemia, familial, 1

ClinGen expert panel — Familial Hypercholesterolemia VCEP

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

PM2 PP4 BP4

Curation rationale (ClinGen, verbatim)

The NM_000527.5 (LDLR):c.1957G>A (p.Val653Ile) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PP4 and BP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 23 February 2024. The supporting evidence is as follows: PM2: This variant is absent in all specified genetic ancestry groups (gnomAD v2.1.1). PP4: Variant meets PM2 and is identified in 1 index case who meets Simon Broome criteria for FH after alternative causes of high cholesterol were excluded, reported in VCI by Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP. Sorbonne Université, Hospital de la Pitié-Salpêtrière, France. BP4: REVEL=0.372, it is below 0.5, splicing evaluation required. MES: A) variant not on limits. B) Variant not on limit creating de novo acceptor; variant is on limit however does not create GT. C) there is not a GT nearby. Variant is not predicted to alter splicing, and result is confirmed by SpliceAI, therefore BP4 is met.

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

Computational evidence

Protein change
AlphaMissense	0.0904	likely benign
REVEL	0.372	indeterminate
SaProt	LLR -7.32	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.3	GERP 2.2, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 42 kb · p 0.91 · regional, not allelic
Overall
CADD	18.62	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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

Grpmax group 0.00167% Admixed American · 1/59,962 alleles

Filtering AF 0.000542% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000428%

Overall 0.000805% 13/1,613,996 alleles · very rare exomes 12/1,461,844 · genomes 1/152,152 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	59,962
European (non-Finnish)	0.00102%	98,333

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.Val653Ile
Coding: c.1957G>A
MANE Select: NM_000527
dbSNP: rs879255085
Type: single nucleotide variant
Location: chr19:11120203 (GRCh38)
Gene constraint: LOEUF 1.091 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.81 · 36 PDB
Residue 653: a β-strand

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.Val653Gly Uncertain significance ★★★ ⚠ same residue
LDLR p.Val653Phe Uncertain significance ★★★ ⚠ same residue
LDLR p.Val653= Benign/Likely benign ★★ same residue
LDLR p.Val653Ala 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
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-val653ile (accessed [today's date]).

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