Is LDLR p.Arg115His (c.344G>A) pathogenic?

LDLR p.Arg115His (c.344G>A) is classified Uncertain significance in LDLR (ClinVar, Expert panel, 16 submitters; last evaluated 2021-06-07). AlphaMissense: likely benign (0.0978); Rare (popmax 0.27%, eas); Associated with hypercholesterolemia, familial, 1.

What condition is associated with LDLR p.Arg115His (c.344G>A)?

LDLR p.Arg115His (c.344G>A) is associated with hypercholesterolemia, familial, 1, familial hypercholesterolemia, homozygous familial hypercholesterolemia (ClinVar).

How common is LDLR p.Arg115His (c.344G>A) in the general population?

LDLR p.Arg115His (c.344G>A) is rare (popmax 0.27%, eas) (gnomAD).

What do computational predictors say about LDLR p.Arg115His (c.344G>A)?

AlphaMissense predicts likely benign (score 0.0978) — an in-silico prediction, not a clinical call.

LDLR p.Arg115His

c.344G>A · rs201102461 · VCV225402

Uncertain significance Expert panel

Classification

Uncertain significance

ClinVar

Review

Expert panel ★★★☆

ClinVar · 16 submitters

AlphaMissense

likely benign

0.0978 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.27%, eas)

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):

PS3

Curation rationale (ClinGen, verbatim)

The NM_000527.5(LDLR):c.344G>A (p.Arg115His) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PS3) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PS3 - Level 1 assays: PMID 12837857: Heterologous cells (COS-7), FACS assays - results - 64% LDLR expression and activity ---- results are below 70% of wild-type, so PS3 is Met.

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

Computational evidence

Protein change
AlphaMissense	0.0978	likely benign
REVEL	0.684	pathogenic-leaning
SaProt	LLR -6.39	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 0.57	GERP -4.1, phastCons 0.12
Regional constraint	o/e 1.00	unconstrained · MANE · 42 kb · p 0.91 · regional, not allelic
Overall
CADD	21.4	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 0.27% East Asian · 121/44,876 alleles

Filtering AF 0.231% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.216%

Overall 0.00824% 133/1,613,420 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.27%	371
Remaining individualsnot grpmax-eligible	0.0032%	31,250
South Asian	0.0022%	45,535
Admixed American	0.00167%	59,994
European (non-Finnish)	0.000593%	168,575

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.Arg115His
Coding: c.344G>A
MANE Select: NM_000527
dbSNP: rs201102461
Type: single nucleotide variant
Location: chr19:11105250 (GRCh38)
Gene constraint: LOEUF 1.091 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.81 · 36 PDB
Residue 115: a β-strand; a disulfide bond; the ldl-receptor class a 3 domain

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 homozygous familial hypercholesterolemia

Similar variants

LDLR p.Arg115Cys Likely pathogenic ★★★ ⚠ same residue
LDLR p.Arg115= Benign 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
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-arg115his (accessed [today's date]).

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