Is LDLR p.Cys104Phe (c.311G>T) pathogenic?

LDLR p.Cys104Phe (c.311G>T) is classified Likely pathogenic in LDLR (ClinVar, Expert panel, 4 submitters; last evaluated 2024-02-23). AlphaMissense: likely pathogenic (0.9469); Absent from gnomAD v4.1; Associated with hypercholesterolemia, familial, 1.

What condition is associated with LDLR p.Cys104Phe (c.311G>T)?

LDLR p.Cys104Phe (c.311G>T) is associated with hypercholesterolemia, familial, 1, familial hypercholesterolemia (ClinVar).

How common is LDLR p.Cys104Phe (c.311G>T) in the general population?

LDLR p.Cys104Phe (c.311G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about LDLR p.Cys104Phe (c.311G>T)?

AlphaMissense predicts likely pathogenic (score 0.9469) — an in-silico prediction, not a clinical call.

LDLR p.Cys104Phe

c.311G>T · rs875989895 · VCV251130

Likely pathogenic Expert panel

Classification

Likely pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.9469 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

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 PM1 PP3 PP4

Curation rationale (ClinGen, verbatim)

The NM_000527.5(LDLR):c.311G>T (p.Cys104Phe) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM1, PM2, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 23 February 2024. The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD v4.0.0). PP3: REVEL = 0.882. PM1: Variant meets PM2 and alters Cys104, one of the cysteine residues listed. PP4: Variant meets PM2 and is identified in at least 1 index case who fulfills clinical criteria for FH from PMID 16159606 (Graham et al., 2005), after alternative causes of high cholesterol were excluded.

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

Computational evidence

Protein change
AlphaMissense	0.9469	likely pathogenic ✓ concordant with ClinVar
REVEL	0.882	moderately pathogenic-leaning
SaProt	LLR -13.00	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 11	GERP 2.5, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 42 kb · p 0.91 · regional, not allelic
Overall
CADD	29.3	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.Cys104Phe
Coding: c.311G>T
MANE Select: NM_000527
dbSNP: rs875989895
Type: single nucleotide variant
Location: chr19:11102784 (GRCh38)
Gene constraint: LOEUF 1.091 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.81 · 36 PDB
Residue 104: a β-strand; a disulfide bond; the ldl-receptor class a 2 domain

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.Cys104Arg Pathogenic/Likely pathogenic ★★ same residue
LDLR p.Cys104Tyr Pathogenic/Likely pathogenic ★★ same residue
LDLR p.Cys104Gly Likely pathogenic ★ same residue
LDLR p.Cys104Ser Pathogenic ★ same residue
LDLR p.Cys104Trp Likely pathogenic ★ same residue
LDLR p.Cys104fs Pathogenic ★★ same residue
LDLR p.Cys104Ter Pathogenic ★ same residue
LDLR c.1186+5G>A 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-cys104phe (accessed [today's date]).

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