Is LDLR p.Ala475Val (c.1424C>T) pathogenic?

LDLR p.Ala475Val (c.1424C>T) is classified Conflicting classifications of pathogenicity in LDLR (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-03-27). AlphaMissense: likely benign (0.201); Very rare (popmax 0.00223%, eas); Associated with Cardiovascular phenotype.

What condition is associated with LDLR p.Ala475Val (c.1424C>T)?

LDLR p.Ala475Val (c.1424C>T) is associated with Cardiovascular phenotype, familial hypercholesterolemia, hypercholesterolemia, familial, 1 (ClinVar).

How common is LDLR p.Ala475Val (c.1424C>T) in the general population?

LDLR p.Ala475Val (c.1424C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about LDLR p.Ala475Val (c.1424C>T)?

AlphaMissense predicts likely benign (score 0.201) — an in-silico prediction, not a clinical call.

LDLR p.Ala475Val

c.1424C>T · rs879254897 · VCV251836

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.201 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.201	likely benign
REVEL	0.732	pathogenic-leaning
SaProt	LLR -8.05	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	GERP 0.97, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 42 kb · p 0.91 · regional, not allelic
Overall
CADD	25.2	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 0.00223% East Asian · 1/44,858 alleles

Overall 0.000186% 3/1,613,854 alleles · very rare exomes 3/1,461,566 · genomes 0/152,288 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,858
African / African-American	0.00133%	75,056
European (non-Finnish)	8.48e-05%	1,179,788

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.Ala475Val
Coding: c.1424C>T
MANE Select: NM_000527
dbSNP: rs879254897
Type: single nucleotide variant
Location: chr19:11113600 (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

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: familial hypercholesterolemia hypercholesterolemia, familial, 1

Similar variants

LDLR p.Ala475Gly Uncertain significance ★ ⚠ same residue
LDLR p.Ala475= Likely benign ★ same residue
LDLR p.Ala475fs 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
LDLR c.190+4A>T 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-ala475val (accessed [today's date]).

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