Is LDLR p.Ala612= (c.1836C>T) pathogenic?

LDLR p.Ala612= (c.1836C>T) is classified Likely benign in LDLR (ClinVar, Expert panel, 19 submitters; last evaluated 2023-04-28). Ultra-rare (popmax 0.0987%, mid); Associated with hypercholesterolemia, familial, 1.

What condition is associated with LDLR p.Ala612= (c.1836C>T)?

LDLR p.Ala612= (c.1836C>T) is associated with hypercholesterolemia, familial, 1, familial hypercholesterolemia (ClinVar).

How common is LDLR p.Ala612= (c.1836C>T) in the general population?

LDLR p.Ala612= (c.1836C>T) is ultra-rare (popmax 0.0987%, mid) (gnomAD).

LDLR p.Ala612=

c.1836C>T · rs143872778 · VCV224618

Likely benign Expert panel

Classification

Likely benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 19 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0987%, mid)

Conditions

hypercholesterolemia, familial, 1

ClinGen expert panel — Familial Hypercholesterolemia VCEP

Likely Benign for hypercholesterolemia, familial. Applied ACMG criteria (verbatim):

BP7 BP4

Curation rationale (ClinGen, verbatim)

The NM_000527.5(LDLR):c.1836C>T (p.Ala612=) variant is classified as likely benign for Familial Hypercholesterolemia by applying evidence code BP4 and BP7 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: BP4 - No REVEL, splicing evaluation required. Functional data on splicing not available. - Variant is exonic and at least 50bp downstream from canonical acceptor site but it does not create GT. - There is a GT nearby. MES scores: variant cryptic = -16.82, wt cryptic = -12.61, canonical donor = 4.48. Ratio variant cryptic/wt cryptic: -16.82/-12.61 = 1.33 --- it is above 1.1 Ratio variant cryptic/canonical donor: -16.82/4.48 = -3.75 --- it is not above 0.9 Variant is not predicted to alter splicing. BP7 - Variant is synonymous and meets BP4.

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

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 -1.9	GERP 1.2
Overall
CADD	9.882	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0987% Middle Eastern · 6/6,082 alleles

Filtering AF 0.0429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0293%

Overall 0.023% 371/1,613,974 alleles · ultra-rare exomes 340/1,461,848 · genomes 31/152,126 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0987%	1,014
European (non-Finnish)	0.0283%	3,533
Remaining individualsnot grpmax-eligible	0.0208%	4,806
Admixed American	0.0117%	8,564
African / African-American	0.00534%	18,728
South Asian	0.00439%	22,772
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,608
East Asian	0.00223%	44,894
Finnishnot grpmax-eligible	0.00156%	64,022

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.Ala612=
Coding: c.1836C>T
MANE Select: NM_000527
dbSNP: rs143872778
Type: single nucleotide variant
Location: chr19:11116989 (GRCh38)
Gene constraint: LOEUF 1.091 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.81 · 36 PDB
Residue 612: a β-strand

Full LDLR gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hypercholesterolemia, familial, 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: familial hypercholesterolemia

Similar variants

LDLR p.Ala612Val Uncertain significance ★★ ⚠ same residue
LDLR p.Ala612Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
LDLR p.Ala612fs Likely pathogenic ★★★ same residue
LDLR p.Ala612Asp Uncertain significance ★ ⚠ same residue
LDLR p.Ala612Pro 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

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-ala612 (accessed [today's date]).

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