Is LDLR p.Asp433Ala (c.1298A>C) pathogenic?

LDLR p.Asp433Ala (c.1298A>C) is classified Likely pathogenic in LDLR (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-22). AlphaMissense: likely pathogenic (0.6935); Very rare (popmax 0.0022%, sas); Associated with familial hypercholesterolemia.

What condition is associated with LDLR p.Asp433Ala (c.1298A>C)?

LDLR p.Asp433Ala (c.1298A>C) is associated with familial hypercholesterolemia (ClinVar).

How common is LDLR p.Asp433Ala (c.1298A>C) in the general population?

LDLR p.Asp433Ala (c.1298A>C) is very rare (popmax 0.0022%, sas) (gnomAD).

What do computational predictors say about LDLR p.Asp433Ala (c.1298A>C)?

AlphaMissense predicts likely pathogenic (score 0.6935) — an in-silico prediction, not a clinical call.

LDLR p.Asp433Ala

c.1298A>C · rs2516004016 · VCV1975487

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6935 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

familial hypercholesterolemia

Computational evidence

Protein change
AlphaMissense	0.6935	likely pathogenic ✓ concordant with ClinVar
REVEL	0.823	moderately pathogenic-leaning
SaProt	LLR -8.27	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 1.5, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 42 kb · p 0.91 · regional, not allelic
Overall
CADD	25.9	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 0.0022% South Asian · 2/91,084 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000137%

Overall 0.000124% 2/1,613,930 alleles · very rare exomes 2/1,461,688 · genomes 0/152,242 · joint denominator

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.Asp433Ala
Coding: c.1298A>C
MANE Select: NM_000527
dbSNP: rs2516004016
Type: single nucleotide variant
Location: chr19:11113389 (GRCh38)
Gene constraint: LOEUF 1.091 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.81 · 36 PDB
Residue 433: a UniProt-annotated variant site (in fhcl1; osaka-3); 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

Similar variants

LDLR p.Asp433His Pathogenic/Likely pathogenic ★★ same residue
LDLR p.Asp433Asn Likely pathogenic ★ same residue
LDLR p.Asp433Tyr Likely pathogenic ★ same residue
LDLR p.Asp433Val Likely 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.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-asp433ala (accessed [today's date]).

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