Is LDLR p.Ala501Val (c.1502C>T) pathogenic?

LDLR p.Ala501Val (c.1502C>T) is classified Pathogenic/Likely pathogenic in LDLR (ClinVar, Multiple submitters, 17 submitters; last evaluated 2026-09-02). AlphaMissense: ambiguous (0.5467); Ultra-rare (popmax 0.0165%, mid); Associated with familial hypercholesterolemia.

What condition is associated with LDLR p.Ala501Val (c.1502C>T)?

LDLR p.Ala501Val (c.1502C>T) is associated with familial hypercholesterolemia, hypercholesterolemia, familial, 1 (ClinVar).

How common is LDLR p.Ala501Val (c.1502C>T) in the general population?

LDLR p.Ala501Val (c.1502C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about LDLR p.Ala501Val (c.1502C>T)?

AlphaMissense predicts ambiguous (score 0.5467) — an in-silico prediction, not a clinical call.

LDLR p.Ala501Val

c.1502C>T · rs755667663 · VCV251874

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 17 submitters

AlphaMissense

ambiguous

0.5467 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

familial hypercholesterolemia

Computational evidence

Protein change
AlphaMissense	0.5467	ambiguous
REVEL	0.806	moderately pathogenic-leaning
SaProt	LLR -8.94	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.5, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 42 kb · p 0.91 · regional, not allelic
Overall
CADD	21.5	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 0.0165% Middle Eastern · 1/6,062 alleles

Filtering AF 0.000292% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.000681% 11/1,614,090 alleles · ultra-rare exomes 11/1,461,826 · genomes 0/152,264 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,062
African / African-American	0.00133%	75,028
South Asian	0.0011%	91,076
European (non-Finnish)	0.000678%	147,498

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.Ala501Val
Coding: c.1502C>T
MANE Select: NM_000527
dbSNP: rs755667663
Type: single nucleotide variant
Location: chr19:11113678 (GRCh38)
Gene constraint: LOEUF 1.091 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.81 · 36 PDB
Residue 501: 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

Also linked: hypercholesterolemia, familial, 1

Similar variants

LDLR p.Ala501Glu Pathogenic/Likely pathogenic ★★ same residue
LDLR p.Ala501Thr Likely pathogenic ★ ⚠ same residue
LDLR p.Ala501Gly Uncertain significance ★ ⚠ same residue
LDLR p.Ala501= Likely benign ★ same residue
LDLR p.Ala501fs Likely pathogenic ★ same residue
LDLR p.Ala501Arg Uncertain significance ★ same residue
LDLR c.1186+5G>A Likely pathogenic ★★★ same condition
LDLR c.1359-1G>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-ala501val (accessed [today's date]).

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