Is LDLR p.Ser846Arg (c.2538C>G) pathogenic?

LDLR p.Ser846Arg (c.2538C>G) is classified Uncertain significance in LDLR (ClinVar, Single submitter, 1 submitter; last evaluated 2026-02-24). AlphaMissense: likely benign (0.1737); Very rare (popmax 6.2e-05%); Associated with familial hypercholesterolemia.

What condition is associated with LDLR p.Ser846Arg (c.2538C>G)?

LDLR p.Ser846Arg (c.2538C>G) is associated with familial hypercholesterolemia (ClinVar).

How common is LDLR p.Ser846Arg (c.2538C>G) in the general population?

LDLR p.Ser846Arg (c.2538C>G) is very rare (popmax 6.2e-05%) (gnomAD).

What do computational predictors say about LDLR p.Ser846Arg (c.2538C>G)?

AlphaMissense predicts likely benign (score 0.1737) — an in-silico prediction, not a clinical call.

LDLR p.Ser846Arg

c.2538C>G · VCV4845232

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1737 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.2e-05%)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

familial hypercholesterolemia

Computational evidence

Protein change
AlphaMissense	0.1737	likely benign
REVEL	0.788	moderately pathogenic-leaning
SaProt	LLR -6.50	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	Δ0.54	donor gain · deltas
Pangolin	Δ0.26	gain · loss 0.07 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 0.28	GERP -1.1, phastCons 0.14
Regional constraint	o/e 1.00	unconstrained · MANE · 42 kb · p 0.91 · regional, not allelic
Overall
CADD	23.9	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 6.2e-05%

Overall 6.2e-05% 1/1,614,056 alleles · very rare exomes 1/1,461,798 · genomes 0/152,258 · 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.Ser846Arg
Coding: c.2538C>G
MANE Select: NM_000527
Type: single nucleotide variant
Location: chr19:11129661 (GRCh38)
Gene constraint: LOEUF 1.091 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.81 · 36 PDB
Residue 846: 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.Ser846del Uncertain significance ★ same residue
LDLR p.Ser846Asn 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.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-ser846arg (accessed [today's date]).

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