Is LDLR p.Val462Ile (c.1384G>A) pathogenic?

LDLR p.Val462Ile (c.1384G>A) is classified Conflicting classifications of pathogenicity in LDLR (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-06-27). AlphaMissense: likely benign (0.07); Ultra-rare (popmax 0.0134%, eas); Associated with familial hypercholesterolemia.

What condition is associated with LDLR p.Val462Ile (c.1384G>A)?

LDLR p.Val462Ile (c.1384G>A) is associated with familial hypercholesterolemia, hypercholesterolemia, familial, 1 (ClinVar).

How common is LDLR p.Val462Ile (c.1384G>A) in the general population?

LDLR p.Val462Ile (c.1384G>A) is ultra-rare (popmax 0.0134%, eas) (gnomAD).

What do computational predictors say about LDLR p.Val462Ile (c.1384G>A)?

AlphaMissense predicts likely benign (score 0.07) — an in-silico prediction, not a clinical call.

LDLR p.Val462Ile

c.1384G>A · rs750363970 · VCV251824

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.07 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0134%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

familial hypercholesterolemia

Computational evidence

Protein change
AlphaMissense	0.07	likely benign
REVEL	0.589	indeterminate
SaProt	LLR -6.93	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 -4.2	GERP -4.1
Regional constraint	o/e 1.00	unconstrained · MANE · 42 kb · p 0.91 · regional, not allelic
Overall
CADD	0.682	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 0.0134% East Asian · 6/44,876 alleles

Filtering AF 0.00579% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00394%

Overall 0.00242% 39/1,613,804 alleles · ultra-rare exomes 37/1,461,690 · genomes 2/152,114 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0134%	7,479
South Asian	0.00549%	18,218
European (non-Finnish)	0.00229%	43,703
Admixed American	0.00167%	59,950

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.Val462Ile
Coding: c.1384G>A
MANE Select: NM_000527
dbSNP: rs750363970
Type: single nucleotide variant
Location: chr19:11113560 (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

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

Also linked: hypercholesterolemia, familial, 1

Similar variants

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
LDLR c.190+4A>T Likely pathogenic ★★★ same condition
LDLR c.2140+1G>A Pathogenic ★★★ same condition
LDLR c.2389+2T>G Pathogenic ★★★ same condition
LDLR c.313+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-val462ile (accessed [today's date]).

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