Is LDLR p.Val653= (c.1959T>C) pathogenic?

LDLR p.Val653= (c.1959T>C) is classified Benign/Likely benign in LDLR (ClinVar, Multiple submitters, 22 submitters; last evaluated 2026-02-04). Common (popmax 52.1%, amr) — too common for a highly-penetrant pathogenic allele; Associated with Cardiovascular phenotype.

What condition is associated with LDLR p.Val653= (c.1959T>C)?

LDLR p.Val653= (c.1959T>C) is associated with Cardiovascular phenotype, familial hypercholesterolemia, hypercholesterolemia, familial, 1 (ClinVar).

LDLR p.Val653=

Q: How common is LDLR p.Val653= (c.1959T>C) in the general population?

LDLR p.Val653= (c.1959T>C) is common (popmax 52.1%, amr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1959T>C · rs5925 · VCV252131

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 22 submitters

gnomAD v4.1

Common

common (popmax 52.1%, amr) — too common for a highly-penetrant pathogenic allele

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.069	GERP -1, phastCons 0.9
Overall
CADD	5.78	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 52.1% Admixed American · 31,260/59,956 alleles

Filtering AF 51.7% ClinGen BA1/BS1 input FAF95, joint · FAF99 51.5%

Overall 43.1% 695,024/1,613,320 alleles · common exomes 637,807/1,461,348 · genomes 57,217/151,972 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	52.1%	2
Finnishnot grpmax-eligible	47.9%	2
Middle Eastern	45.5%	2
European (non-Finnish)	44.7%	2
Ashkenazi Jewishnot grpmax-eligible	43.4%	2
South Asian	43.4%	2
Remaining individualsnot grpmax-eligible	42.2%	2
Amishnot grpmax-eligible	34.7%	3
African / African-American	19.7%	5
East Asian	19.6%	5

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.Val653=
Coding: c.1959T>C
MANE Select: NM_000527
dbSNP: rs5925
Type: single nucleotide variant
Location: chr19:11120205 (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

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

Also linked: familial hypercholesterolemia hypercholesterolemia, familial, 1

Similar variants

LDLR p.Val653Gly Uncertain significance ★★★ ⚠ same residue
LDLR p.Val653Ile Uncertain significance ★★★ ⚠ same residue
LDLR p.Val653Phe Uncertain significance ★★★ ⚠ 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-val653 (accessed [today's date]).

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