Is LDLR p.Ser213Arg (c.639C>G) pathogenic?

LDLR p.Ser213Arg (c.639C>G) is classified Uncertain significance in LDLR (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-03-06). AlphaMissense: likely benign (0.3228); Very rare (popmax 0.00266%, afr); Associated with familial hypercholesterolemia.

What condition is associated with LDLR p.Ser213Arg (c.639C>G)?

LDLR p.Ser213Arg (c.639C>G) is associated with familial hypercholesterolemia (ClinVar).

How common is LDLR p.Ser213Arg (c.639C>G) in the general population?

LDLR p.Ser213Arg (c.639C>G) is very rare (popmax 0.00266%, afr) (gnomAD).

What do computational predictors say about LDLR p.Ser213Arg (c.639C>G)?

AlphaMissense predicts likely benign (score 0.3228) — an in-silico prediction, not a clinical call.

LDLR p.Ser213Arg

c.639C>G · rs760616999 · VCV926960

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.3228 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00266%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

familial hypercholesterolemia

Computational evidence

Protein change
AlphaMissense	0.3228	likely benign
REVEL	0.637	indeterminate
SaProt	LLR -8.08	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.3	GERP -1, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 42 kb · p 0.91 · regional, not allelic
Overall
CADD	20.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00266% African / African-American · 2/75,064 alleles

Filtering AF 0.000442% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000124% 2/1,613,606 alleles · very rare exomes 2/1,461,280 · genomes 0/152,326 · 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.Ser213Arg
Coding: c.639C>G
MANE Select: NM_000527
dbSNP: rs760616999
Type: single nucleotide variant
Location: chr19:11105545 (GRCh38)
Gene constraint: LOEUF 1.091 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.81 · 36 PDB
Residue 213: the 'binding to getah virus e1-e2 spike glycoproteins' region; an α-helix; the ldl-receptor class a 5 domain

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.Ser213Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
LDLR p.Ser213fs Pathogenic/Likely pathogenic ★★ same residue
LDLR p.Ser213Ile 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

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-ser213arg (accessed [today's date]).

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