Is LDLR p.Ala540Ser (c.1618G>T) pathogenic?

LDLR p.Ala540Ser (c.1618G>T) is classified Likely pathogenic in LDLR (ClinVar, Expert panel, 3 submitters; last evaluated 2022-08-28). AlphaMissense: likely benign (0.1495); Absent from gnomAD v4.1; Associated with hypercholesterolemia, familial, 1.

What condition is associated with LDLR p.Ala540Ser (c.1618G>T)?

LDLR p.Ala540Ser (c.1618G>T) is associated with hypercholesterolemia, familial, 1 (ClinVar).

How common is LDLR p.Ala540Ser (c.1618G>T) in the general population?

LDLR p.Ala540Ser (c.1618G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about LDLR p.Ala540Ser (c.1618G>T)?

AlphaMissense predicts likely benign (score 0.1495) — an in-silico prediction, not a clinical call.

LDLR p.Ala540Ser

c.1618G>T · rs769370816 · VCV251938

Likely pathogenic Expert panel

Classification

Likely pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1495 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hypercholesterolemia, familial, 1

ClinGen expert panel — Familial Hypercholesterolemia VCEP

Likely Pathogenic for hypercholesterolemia, familial. Applied ACMG criteria (verbatim):

PM2 PP3 PP4 PM5

Curation rationale (ClinGen, verbatim)

The NM_000527.5(LDLR):c.1618G>T (p.Ala540Ser) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes PM2, PM5, PP3, 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 - variant was not identified in gnomAD (gnomAD v2.1.1), so met. PM5 - 1 other missense variant in the same codon: - NM_000527.5(LDLR):c.1618G>A (p.Ala540Thr) - 2 stars, Pathogenic/Likely pathogenic - Pathogenic by these guidelines so PM5 is met. PP3 - REVEL = 0.821. It is above 0.75, so PP3 is met. PP4 - variant meets PM2 and was identified in: - at least 1 index case with definite FH ((in the paper: "All patients were clinically diagnosed with definite heterozygous hypercholesterolemia by cardiologists and internists using a uniform protocol and internationally accepted criteria [Defesche, 2000].") from PMID 16250003 (Fouchier et al., 2005), The Netherlands. so PP4 is met.

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

Computational evidence

Protein change
AlphaMissense	0.1495	likely benign ⚠ discordant with ClinVar
REVEL	0.821	moderately pathogenic-leaning
SaProt	LLR -9.57	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 11	GERP 2.5, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 42 kb · p 0.91 · regional, not allelic
Overall
CADD	25.7	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: LDLR
Protein: p.Ala540Ser
Coding: c.1618G>T
MANE Select: NM_000527
dbSNP: rs769370816
Type: single nucleotide variant
Location: chr19:11116125 (GRCh38)
Gene constraint: LOEUF 1.091 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.81 · 36 PDB

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.Ala540Thr Pathogenic ★★★ same residue
LDLR p.Ala540Val Likely pathogenic ★ same residue
LDLR p.Ala540del 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.1705+2T>C Likely pathogenic ★★★ same condition
LDLR c.190+4A>T 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-ala540ser (accessed [today's date]).

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