Is LDLR p.Cys318Phe (c.953G>T) pathogenic?

LDLR p.Cys318Phe (c.953G>T) is classified Pathogenic/Likely pathogenic in LDLR (ClinVar, Multiple submitters, 10 submitters; last evaluated 2025-11-26). AlphaMissense: likely pathogenic (0.9875); Absent from gnomAD v4.1; Associated with Cardiovascular phenotype.

What condition is associated with LDLR p.Cys318Phe (c.953G>T)?

LDLR p.Cys318Phe (c.953G>T) is associated with Cardiovascular phenotype, familial hypercholesterolemia, hypercholesterolemia, familial, 1 (ClinVar).

How common is LDLR p.Cys318Phe (c.953G>T) in the general population?

LDLR p.Cys318Phe (c.953G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about LDLR p.Cys318Phe (c.953G>T)?

AlphaMissense predicts likely pathogenic (score 0.9875) — an in-silico prediction, not a clinical call.

LDLR p.Cys318Phe

c.953G>T · rs879254739 · VCV251572

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 10 submitters

AlphaMissense

likely pathogenic

0.9875 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.9875	likely pathogenic ✓ concordant with ClinVar · top 7% in LDLR
REVEL	0.956	strongly pathogenic-leaning
SaProt	LLR -15.13	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 2.4, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 42 kb · p 0.91 · regional, not allelic
Overall
CADD	28.9	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.Cys318Phe
Coding: c.953G>T
MANE Select: NM_000527
dbSNP: rs879254739
Type: single nucleotide variant
Location: chr19:11110664 (GRCh38)
Gene constraint: LOEUF 1.091 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.81 · 36 PDB
Residue 318: the egf-like 1 domain; a UniProt-annotated variant site (in fhcl1; trieste); a UniProt-annotated variant site (in fhcl1); a UniProt-annotated variant site (in fhcl1; mexico-1; leads to a defect in the intracellular transport of the receptor); an α-helix; a disulfide bond

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

Disease context

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: familial hypercholesterolemia hypercholesterolemia, familial, 1

Similar variants

LDLR p.Cys318Arg Pathogenic/Likely pathogenic ★★ same residue
LDLR p.Cys318Ter Pathogenic/Likely pathogenic ★★ same residue
LDLR p.Cys318Tyr 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
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-cys318phe (accessed [today's date]).

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