Is LDLR p.Arg124Trp (c.370C>T) pathogenic?

LDLR p.Arg124Trp (c.370C>T) is classified Conflicting classifications of pathogenicity in LDLR (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2016-10-31). AlphaMissense: likely benign (0.1642); Very rare (popmax 0.0011%, sas); Associated with hypercholesterolemia, familial, 1.

What condition is associated with LDLR p.Arg124Trp (c.370C>T)?

LDLR p.Arg124Trp (c.370C>T) is associated with hypercholesterolemia, familial, 1, familial hypercholesterolemia (ClinVar).

How common is LDLR p.Arg124Trp (c.370C>T) in the general population?

LDLR p.Arg124Trp (c.370C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about LDLR p.Arg124Trp (c.370C>T)?

AlphaMissense predicts likely benign (score 0.1642) — an in-silico prediction, not a clinical call.

LDLR p.Arg124Trp

c.370C>T · rs879254498 · VCV251185

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1642 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hypercholesterolemia, familial, 1

Computational evidence

Protein change
AlphaMissense	0.1642	likely benign
REVEL	0.565	indeterminate
SaProt	LLR -9.09	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.42	GERP -2.2
Regional constraint	o/e 1.00	unconstrained · MANE · 42 kb · p 0.91 · regional, not allelic
Overall
CADD	19.85	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 0.0011% South Asian · 1/91,078 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.00031% 5/1,613,718 alleles · very rare exomes 5/1,461,394 · genomes 0/152,324 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,078
European (non-Finnish)	0.000339%	295,006

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.Arg124Trp
Coding: c.370C>T
MANE Select: NM_000527
dbSNP: rs879254498
Type: single nucleotide variant
Location: chr19:11105276 (GRCh38)
Gene constraint: LOEUF 1.091 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.81 · 36 PDB
Residue 124: an α-helix; 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

Similar variants

LDLR p.Arg124Pro Uncertain significance ★★ ⚠ same residue
LDLR p.Arg124Gly Likely benign ★ same residue
LDLR p.Arg124fs Pathogenic ★★ same residue
LDLR p.Arg124delinsAlaThrMetGlySerAlaSerLeuProArgTrpGluVal Uncertain significance ★★ same residue
LDLR p.Arg124= Likely 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

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-arg124trp (accessed [today's date]).

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