Is LDLR p.Asp342His (c.1024G>C) pathogenic?

LDLR p.Asp342His (c.1024G>C) is classified Uncertain significance in LDLR (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-10). AlphaMissense: likely benign (0.1062); Ultra-rare (popmax 0.0165%, mid); Associated with hypercholesterolemia, familial, 1.

What condition is associated with LDLR p.Asp342His (c.1024G>C)?

LDLR p.Asp342His (c.1024G>C) is associated with hypercholesterolemia, familial, 1 (ClinVar).

How common is LDLR p.Asp342His (c.1024G>C) in the general population?

LDLR p.Asp342His (c.1024G>C) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about LDLR p.Asp342His (c.1024G>C)?

AlphaMissense predicts likely benign (score 0.1062) — an in-silico prediction, not a clinical call.

LDLR p.Asp342His

c.1024G>C · rs139361635 · VCV3073453

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1062 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hypercholesterolemia, familial, 1

Computational evidence

Protein change
AlphaMissense	0.1062	likely benign
REVEL	0.445	indeterminate
SaProt	LLR -6.53	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 -0.02	GERP -4.9
Regional constraint	o/e 1.00	unconstrained · MANE · 42 kb · p 0.91 · regional, not allelic
Overall
CADD	8.762	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 0.0165% Middle Eastern · 1/6,062 alleles

Overall 0.000186% 3/1,613,774 alleles · ultra-rare exomes 3/1,461,476 · genomes 0/152,298 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,062
Remaining individualsnot grpmax-eligible	0.0016%	62,496
African / African-American	0.00133%	75,064

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.Asp342His
Coding: c.1024G>C
MANE Select: NM_000527
dbSNP: rs139361635
Type: single nucleotide variant
Location: chr19:11110735 (GRCh38)
Gene constraint: LOEUF 1.091 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.81 · 36 PDB
Residue 342: the egf-like 1 domain; a UniProt-annotated variant site (in fhcl1; uncertain significance; new york-1); a UniProt-annotated variant site (in fhcl1; benign); a β-strand

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

Similar variants

LDLR p.Asp342Tyr Uncertain significance ★★★ ⚠ same residue
LDLR p.Asp342Asn Benign ★★★ same residue
LDLR p.Asp342= Likely benign ★★ same residue
LDLR p.Asp342Glu Conflicting classifications of pathogenicity ★ ⚠ 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-asp342his (accessed [today's date]).

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