Is LDLR p.Ser849= (c.2547G>A) pathogenic?

LDLR p.Ser849= (c.2547G>A) is classified Uncertain significance in LDLR (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-08-07). Very rare (popmax 0.00167%, amr); Associated with familial hypercholesterolemia.

What condition is associated with LDLR p.Ser849= (c.2547G>A)?

LDLR p.Ser849= (c.2547G>A) is associated with familial hypercholesterolemia (ClinVar).

How common is LDLR p.Ser849= (c.2547G>A) in the general population?

LDLR p.Ser849= (c.2547G>A) is very rare (popmax 0.00167%, amr) (gnomAD).

LDLR p.Ser849=

c.2547G>A · rs1249903899 · VCV848272

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Conditions

familial hypercholesterolemia

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 -1.3, phastCons 1
Overall
CADD	16.34	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/59,986 alleles

Filtering AF 0.000359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00026%

Overall 0.00062% 10/1,613,878 alleles · very rare exomes 10/1,461,702 · genomes 0/152,176 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	59,986
European (non-Finnish)	0.000763%	131,107

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.Ser849=
Coding: c.2547G>A
MANE Select: NM_000527
dbSNP: rs1249903899
Type: single nucleotide variant
Location: chr19:11129670 (GRCh38)
Gene constraint: LOEUF 1.091 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.81 · 36 PDB
Residue 849: the 'required for mylip-triggered down-regulation of ldlr' region

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.Ser849Ter Likely pathogenic ★★★ same residue
LDLR p.Ser849Leu Conflicting classifications of pathogenicity ★ ⚠ 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
LDLR c.2140+1G>A Pathogenic ★★★ same condition
LDLR c.2389+2T>G 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-ser849 (accessed [today's date]).

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