Is LDLR p.Arg78His (c.233G>A) pathogenic?

LDLR p.Arg78His (c.233G>A) is classified Uncertain significance in LDLR (ClinVar, Expert panel, 13 submitters; last evaluated 2022-08-28). AlphaMissense: likely benign (0.0796); Ultra-rare (popmax 0.0106%, nfe); Associated with hypercholesterolemia, familial, 1.

What condition is associated with LDLR p.Arg78His (c.233G>A)?

LDLR p.Arg78His (c.233G>A) is associated with hypercholesterolemia, familial, 1, familial hypercholesterolemia (ClinVar).

How common is LDLR p.Arg78His (c.233G>A) in the general population?

LDLR p.Arg78His (c.233G>A) is ultra-rare (popmax 0.0106%, nfe) (gnomAD).

What do computational predictors say about LDLR p.Arg78His (c.233G>A)?

AlphaMissense predicts likely benign (score 0.0796) — an in-silico prediction, not a clinical call.

LDLR p.Arg78His

c.233G>A · rs146675823 · VCV251085

Uncertain significance Expert panel

Classification

Uncertain significance

ClinVar

Review

Expert panel ★★★☆

ClinVar · 13 submitters

AlphaMissense

likely benign

0.0796 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0106%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hypercholesterolemia, familial, 1

ClinGen expert panel — Familial Hypercholesterolemia VCEP

Uncertain Significance for hypercholesterolemia, familial. Applied ACMG criteria (verbatim):

PM2 PS4_Supporting PP3 PP4

Curation rationale (ClinGen, verbatim)

The NM_000527.5(LDLR):c.233G>A (p.Arg78His) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PM2, PP3, PS4_Supporting and PP4 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: PM2 - PopMax MAF = 0.0001202 (0.012%) in African/African American exomes+genomes (gnomAD v2.1.1). It is below 0.02%, so PM2 is met. PP3 - REVEL = 0.806. It is above 0.75, so PP3 is met. PS4_supporting - variant meets PM2 and was identified in: - 1 index case with SB criteria of FH from PMID 31993549 (Garg et al., 2019), North America; - 1 index case with DLCN at least 8 (TC>10mmol/L and xanthomas) from PMID 27830735 (Jiang et al. 2016), China; - 1 index case with MEDPED criteria of FH from Benyahya et al. (2010) (paper cited in HGMD), Morocco; 3 unrelated index cases, so PS4_Supporting is met. PP4 - variant meets PM2 and was identified in 3 unrelated index cases who fulfill clinical criteria for FH after alternative causes of high cholesterol were excluded (please see PS4 for details), so PP4 is met.

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

Computational evidence

Protein change
AlphaMissense	0.0796	likely benign
REVEL	0.806	moderately pathogenic-leaning
SaProt	LLR -7.29	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.003	GERP -3.2
Regional constraint	o/e 1.00	unconstrained · MANE · 42 kb · p 0.91 · regional, not allelic
Overall
CADD	21.1	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 0.0106% European (non-Finnish) · 125/1,179,760 alleles

Filtering AF 0.00906% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00844%

Overall 0.0083% 134/1,613,666 alleles · ultra-rare exomes 126/1,461,474 · genomes 8/152,192 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0106%	9,438
Remaining individualsnot grpmax-eligible	0.0064%	15,615
African / African-American	0.00534%	18,734
Admixed American	0.00167%	59,966

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.Arg78His
Coding: c.233G>A
MANE Select: NM_000527
dbSNP: rs146675823
Type: single nucleotide variant
Location: chr19:11102706 (GRCh38)
Gene constraint: LOEUF 1.091 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.81 · 36 PDB
Residue 78: a β-strand; the ldl-receptor class a 2 domain; a UniProt-annotated variant site (in fhcl1; uncertain significance)

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.Arg78Cys Uncertain significance ★★★ ⚠ same residue
LDLR p.Arg78Leu Uncertain significance ★ ⚠ same residue
LDLR p.Arg78= Likely benign ★ same residue
LDLR p.Arg78fs Pathogenic ★ 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-arg78his (accessed [today's date]).

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