# NM_000527.5(LDLR):c.1190C>T (p.Ser397Phe)

https://sugi.bio/variant/ldlr-p-ser397phe

## Summary

**LDLR p.Ser397Phe (c.1190C>T)** is classified **Uncertain significance** in LDLR (ClinVar, Expert panel, 2 submitters; last evaluated 2023-06-23). AlphaMissense: likely benign (0.3086); Very rare (popmax 0.0033%, sas); Associated with hypercholesterolemia, familial, 1.

**At a glance:** Uncertain significance · review: Expert panel · rsID rs2077406646 · 2 submitters · 2 linked conditions · AlphaMissense likely benign · very rare (popmax 0.0033%, sas)

## For patients & families {#patients}

This is a change in the LDLR gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 submitters, and is linked to hypercholesterolemia, familial, 1.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Clinical trials | 28 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0024574/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [LDLR](https://sugi.bio/atlas/gene/LDLR/) |
| Protein change (HGVS p.) | p.Ser397Phe |
| Coding change (HGVS c.) | c.1190C>T |
| MANE Select transcript | [NM_000527](https://www.ncbi.nlm.nih.gov/nuccore/NM_000527) |
| dbSNP | [rs2077406646](https://www.ncbi.nlm.nih.gov/snp/rs2077406646/) |
| Variant type | single nucleotide variant |
| Location | chr19:11113281-11113281 (GRCh38) |
| ClinVar | [VCV925475](https://www.ncbi.nlm.nih.gov/clinvar/variation/925475/) |

**All HGVS expressions:** `LRG_274:g.28901C>T`, `LRG_274t1:c.1190C>T`, `NC_000019.10:g.11113281C>T`, `NC_000019.9:g.11223957C>T`, `NG_009060.1:g.28901C>T`, `NM_000527.5:c.1190C>T`, `NM_001195798.2:c.1190C>T`, `NM_001195799.2:c.1067C>T`, `NM_001195800.2:c.686C>T`, `NM_001195803.2:c.809C>T`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely benign** (0.3086)
- REVEL 0.619 (indeterminate)
- SaProt LLR -10.137 (damaging) — differs from AlphaMissense
- → **In-silico consensus:** SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate
- Conservation: phyloP 1.184, GERP 0.87 — weakly conserved position
- CADD: **PHRED 21.4**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- Regional missense constraint: **o/e 1.00** across the covering region of the MANE Select transcript (11,089,549–11,131,313), spanning 41,764 bp. Chi-square p 0.91. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.0033%** (sas) · FAF95 0.000876% · FAF99 0.000443% · 3/91,014 in the highest group · 3/1,612,692 alleles overall — very rare (popmax 0.0033%, sas).

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**LDLR** population constraint: LOEUF 1.091, pLI 1.2477e-30, missense-Z 0.60522; ClinGen dosage — haploinsufficiency 3/3, triplosensitivity 0/3. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **hypercholesterolemia, familial, 1** — Definitive (SD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 75.81, 29% of residues very-high.

**36 experimental structure(s)** (PDB): [1AJJ](https://www.rcsb.org/structure/1AJJ), [1D2J](https://www.rcsb.org/structure/1D2J), [1F5Y](https://www.rcsb.org/structure/1F5Y), [1F8Z](https://www.rcsb.org/structure/1F8Z), [1HJ7](https://www.rcsb.org/structure/1HJ7), [1HZ8](https://www.rcsb.org/structure/1HZ8) — incl. mutant structure 2W2N.

## What this gene does {#gene-function}

*Describes the biological roles of LDLR (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** LDLR's established molecular role includes protease binding.


### Pathways affected {#pathways}

LDLR participates in **5 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Cargo recognition for clathrin-mediated endocytosis](https://reactome.org/content/detail/R-HSA-8856825) | curated |
| [Clathrin-mediated endocytosis](https://reactome.org/content/detail/R-HSA-8856828) | curated |
| [LDL clearance](https://reactome.org/content/detail/R-HSA-8964038) | curated |
| [Chylomicron clearance](https://reactome.org/content/detail/R-HSA-8964026) | electronic |
| [Retinoid metabolism and transport](https://reactome.org/content/detail/R-HSA-975634) | electronic |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** protease binding, low-density lipoprotein particle receptor activity, low-density lipoprotein particle binding, very-low-density lipoprotein particle receptor activity, identical protein binding, molecular adaptor activity.

**Biological process:** negative regulation of receptor recycling, long-term memory, negative regulation of low-density lipoprotein particle clearance, intestinal cholesterol absorption, cholesterol transport, low-density lipoprotein particle clearance.

## Clinical significance {#significance}

**Uncertain significance** — review status Expert panel *(reviewed by expert panel)*, last evaluated 2023-06-23.

**Submitter consensus:** conflicting (1 Uncertain significance, 1 Uncertain Significance).

**Submission history:** 2 submissions (2023); classifications have been stable.

**ClinGen expert panel:** Uncertain Significance — Familial Hypercholesterolemia VCEP (hypercholesterolemia, familial). *Expert-panel curated (ACMG); the highest ClinVar review tier.*
**Applied ACMG criteria (met):** `PM2`.
*Considered but not met:* `PS1`, `PP3`, `BS1`, `PM5`, `BP4`, `BA1`.
Inheritance: Semidominant inheritance.

> **Curation rationale (ClinGen, verbatim):** The NM_000527.5(LDLR):c.1190C>T (p.Ser397Phe) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence code PM2 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 23 June 2023. The supporting evidence is as follows:  PM2: This variant is absent from gnomAD (gnomAD v2.1.1).
*Source: https://cspec.clinicalgenome.org/cspec/ui/svi/affiliation/50004 · approved 2023-06-23 · [ClinGen Evidence Repository](https://erepo.genome.network/evrepo/ui/classification/1461d879-5453-46e8-824d-6d7214d2b247).*
*These are ClinGen's applied codes, reported verbatim — Sugi Variant does not re-tally or combine them into its own classification.*

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Color Diagnostics, LLC DBA Color Health | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-12-05 |
| ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel | Uncertain Significance | reviewed by expert panel | curation | 2023-06-23 |

## Associated conditions {#conditions}

[hypercholesterolemia, familial, 1](https://sugi.bio/atlas/disease/hypercholesterolemia-familial-1/), [familial hypercholesterolemia](https://sugi.bio/atlas/disease/familial-hypercholesterolemia/).

**Reported phenotype names (ClinVar):** Hypercholesterolemia, familial, 1, Familial hypercholesterolemia, Familial hypercholesterolemias, Familial hypercholesterolaemia, LDL RECEPTOR DISORDER, Hyperlipoproteinemia Type IIa, HYPER-LOW-DENSITY-LIPOPROTEINEMIA, HYPERCHOLESTEROLEMIC XANTHOMATOSIS, FAMILIAL, Fredrickson type IIa hyperlipoproteinemia, Hyperlipoproteinemia type 2.

## Similar variants {#similar}

Related LDLR variant pages (same residue, condition, or type): [LDLR p.Ser397Pro](/variant/ldlr-p-ser397pro), [LDLR p.Ser397Thr](/variant/ldlr-p-ser397thr), [LDLR p.Ser397=](/variant/ldlr-p-ser397), [LDLR c.1186+5G>A](/variant/ldlr-c-1186-plus-5g-a), [LDLR c.1359-1G>A](/variant/ldlr-c-1359-minus-1g-a), [LDLR c.1359-5C>G](/variant/ldlr-c-1359-minus-5c-g), [LDLR c.1705+2T>C](/variant/ldlr-c-1705-plus-2t-c), [LDLR c.190+4A>T](/variant/ldlr-c-190-plus-4a-t).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 925475). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*