Is LDLR p.Cys143Phe (c.428G>T) pathogenic?

LDLR p.Cys143Phe (c.428G>T) is classified Pathogenic/Likely pathogenic in LDLR (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-01-08). AlphaMissense: likely pathogenic (0.9475); No allele count reported in gnomAD v4.1 (AN 1,613,904); Associated with familial hypercholesterolemia.

What condition is associated with LDLR p.Cys143Phe (c.428G>T)?

LDLR p.Cys143Phe (c.428G>T) is associated with familial hypercholesterolemia, hypercholesterolemia, familial, 1 (ClinVar).

How common is LDLR p.Cys143Phe (c.428G>T) in the general population?

LDLR p.Cys143Phe (c.428G>T) is no allele count reported in gnomAD v4.1 (AN 1,613,904) (gnomAD).

What do computational predictors say about LDLR p.Cys143Phe (c.428G>T)?

AlphaMissense predicts likely pathogenic (score 0.9475) — an in-silico prediction, not a clinical call.

LDLR p.Cys143Phe

c.428G>T · rs879254522 · VCV523723

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.9475 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,613,904)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

familial hypercholesterolemia

Computational evidence

Protein change
AlphaMissense	0.9475	likely pathogenic ✓ concordant with ClinVar
REVEL	0.952	strongly pathogenic-leaning
SaProt	LLR -13.41	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 12	GERP 2.5, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 42 kb · p 0.91 · regional, not allelic
Overall
CADD	25.8	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

No allele count reported in gnomAD v4.1 (AN 1,613,904). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: LDLR
Protein: p.Cys143Phe
Coding: c.428G>T
MANE Select: NM_000527
dbSNP: rs879254522
Type: single nucleotide variant
Location: chr19:11105334 (GRCh38)
Gene constraint: LOEUF 1.091 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.81 · 36 PDB
Residue 143: an α-helix; a disulfide bond; the ldl-receptor class a 3 domain; a UniProt-annotated variant site (in fhcl1)

Full LDLR gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

familial hypercholesterolemia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hypercholesterolemia, familial, 1

Similar variants

LDLR p.Cys143Arg Pathogenic/Likely pathogenic ★★ same residue
LDLR p.Cys143Gly Pathogenic/Likely pathogenic ★★ same residue
LDLR p.Cys143Ser Pathogenic/Likely pathogenic ★★ same residue
LDLR p.Cys143Ter Pathogenic ★★ same residue
LDLR p.Cys143Tyr Pathogenic/Likely 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

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-cys143phe (accessed [today's date]).

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