Is LDLR p.Ser580Phe (c.1739C>T) pathogenic?

LDLR p.Ser580Phe (c.1739C>T) is classified Likely pathogenic in LDLR (ClinVar, Expert panel, 7 submitters; last evaluated 2023-11-07). AlphaMissense: likely pathogenic (0.9377); Very rare (popmax 8.47e-05%, nfe); Associated with hypercholesterolemia, familial, 1.

What condition is associated with LDLR p.Ser580Phe (c.1739C>T)?

LDLR p.Ser580Phe (c.1739C>T) is associated with hypercholesterolemia, familial, 1, familial hypercholesterolemia (ClinVar).

How common is LDLR p.Ser580Phe (c.1739C>T) in the general population?

LDLR p.Ser580Phe (c.1739C>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about LDLR p.Ser580Phe (c.1739C>T)?

AlphaMissense predicts likely pathogenic (score 0.9377) — an in-silico prediction, not a clinical call.

LDLR p.Ser580Phe

c.1739C>T · rs934496989 · VCV438325

Likely pathogenic Expert panel

Classification

Likely pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 7 submitters

AlphaMissense

likely pathogenic

0.9377 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hypercholesterolemia, familial, 1

ClinGen expert panel — Familial Hypercholesterolemia VCEP

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

PM2 PS4_Supporting PS3_Supporting PP1 PP3 PP4

Curation rationale (ClinGen, verbatim)

The NM_000527.5(LDLR):c.1739C>T (p.Ser580Phe) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PP1, PP3, PP4, PS3_Supporting and PS4_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 7 November 2023. The supporting evidence is as follows: PM2: PopMax MAF = 0.00001 (0.001%) in European (Non-Finnish) exomes+genomes (gnomAD v2.1.1). PP3: REVEL=0.907. PS3_Supporting: Level 3 assay: PMID 35474963 (Pfisterer SG et al., 2022): Heterozygous patient monocytes and lymphocytes. 25-50% of control low-density lipoprotein particle uptake and LDLR surface expression. PS4_Supporting, PP4: Variant meets PM2 and is identified in at least 3 unrelated index cases who fulfill DLCN score >=6 (1 case from Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon, Lyon, France; 2 cases from Research Lab of Molecular Genetics of Lipid Metabolism, Italy - Prof. M. Arca). PP1: Variant segregates with FH phenotype in 2 informative meioses identified by Research Lab of Molecular Genetics of Lipid Metabolism, Italy - Prof. M. Arca. 1 affected family member has the variant and 1 unaffected family member does not have the variant.

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

Computational evidence

Protein change
AlphaMissense	0.9377	likely pathogenic ✓ concordant with ClinVar
REVEL	0.907	moderately pathogenic-leaning
SaProt	LLR -14.12	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	GERP 1.4, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 42 kb · p 0.91 · regional, not allelic
Overall
CADD	27.7	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

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,012 alleles

Overall 6.2e-05% 1/1,614,064 alleles · very rare exomes 1/1,461,808 · genomes 0/152,256 · joint denominator

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.Ser580Phe
Coding: c.1739C>T
MANE Select: NM_000527
dbSNP: rs934496989
Type: single nucleotide variant
Location: chr19:11116892 (GRCh38)
Gene constraint: LOEUF 1.091 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.81 · 36 PDB
Residue 580: a turn

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.Ser580Cys Uncertain significance ★★★ ⚠ same residue
LDLR p.Ser580Pro Uncertain significance ★★★ ⚠ same residue
LDLR p.Ser580Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
LDLR p.Ser580fs 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-ser580phe (accessed [today's date]).

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