# NM_000527.5(LDLR):c.2053C>T (p.Pro685Ser)

https://sugi.bio/variant/ldlr-p-pro685ser

## Summary

**LDLR p.Pro685Ser (c.2053C>T)** is classified **Pathogenic/Likely pathogenic** in LDLR (ClinVar, Multiple submitters, 2 submitters; last evaluated 2016-03-25). AlphaMissense: likely pathogenic (0.7206); Absent from gnomAD v4.1; Associated with hypercholesterolemia, familial, 1.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs2569548 · 2 submitters · 1 linked condition · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the LDLR gene that is considered likely disease-causing, 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.Pro685Ser |
| Coding change (HGVS c.) | c.2053C>T |
| MANE Select transcript | [NM_000527](https://www.ncbi.nlm.nih.gov/nuccore/NM_000527) |
| dbSNP | [rs2569548](https://www.ncbi.nlm.nih.gov/snp/rs2569548/) |
| Variant type | single nucleotide variant |
| Location | chr19:11120435-11120435 (GRCh38) |
| ClinVar | [VCV252194](https://www.ncbi.nlm.nih.gov/clinvar/variation/252194/) |

**All HGVS expressions:** `LRG_274:g.36055C>T`, `LRG_274t1:c.2053C>T`, `NC_000019.10:g.11120435C>T`, `NC_000019.9:g.11231111C>T`, `NG_009060.1:g.36055C>T`, `NM_000527.5:c.2053C>T`, `NM_001195798.2:c.2053C>T`, `NM_001195799.2:c.1930C>T`, `NM_001195800.2:c.1549C>T`, `NM_001195803.2:c.1606+202C>T`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- AlphaMissense **likely pathogenic** (0.7206) — concordant with the pathogenic call
- REVEL 0.84 (moderately pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -12.112 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 7.547, GERP 2.54, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 24.8**. 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: **below the reporting threshold**. This position is scored for a different substitution (C>G, Δ0.21 acceptor loss), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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}

Residue **685** lies in the egf-like 3 domain; a UniProt-annotated variant site (in fhcl1; gujerat/zambia/belgian/dutch/sweden/japan).

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. p.Pro685Ser falls in the egf-like 3 domain.


### 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}

**Pathogenic/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2016-03-25.

**Submitter consensus:** conflicting (1 Likely pathogenic, 1 Pathogenic).

**Submission history:** 2 submissions (2016); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| LDLR-LOVD, British Heart Foundation | Likely pathogenic | criteria provided, single submitter | literature only | 2016-03-25 |
| Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge | Pathogenic | criteria provided, single submitter | research | 2016-03-01 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Hypercholesterolemia, familial, 1, LDL RECEPTOR DISORDER, Hyperlipoproteinemia Type IIa, HYPER-LOW-DENSITY-LIPOPROTEINEMIA, HYPERCHOLESTEROLEMIC XANTHOMATOSIS, FAMILIAL, Fredrickson type IIa hyperlipoproteinemia, Hyperlipoproteinemia type 2, Hyper-beta-lipoproteinemia, Hyperlipoproteinemia Type II, HYPERCHOLESTEROLEMIA, FAMILIAL, MODIFIER OF.

## Same-residue context {#hotspot}

Residue **685** carries **6 other pathogenic ClinVar variants** — a recurrently-mutated position: [LDLR p.Pro685Thr](/variant/ldlr-p-pro685thr), [LDLR p.Pro685fs](/variant/ldlr-p-pro685fs), [LDLR p.Pro685Arg](/variant/ldlr-p-pro685arg), [LDLR p.Pro685Ala](/variant/ldlr-p-pro685ala), [LDLR p.Pro685Leu](/variant/ldlr-p-pro685leu), [LDLR p.Pro685Gln](/variant/ldlr-p-pro685gln). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related LDLR variant pages (same residue, condition, or type): [LDLR p.Pro685Gln](/variant/ldlr-p-pro685gln), [LDLR p.Pro685Leu](/variant/ldlr-p-pro685leu), [LDLR p.Pro685Thr](/variant/ldlr-p-pro685thr), [LDLR p.Pro685=](/variant/ldlr-p-pro685), [LDLR p.Pro685fs](/variant/ldlr-p-pro685fs), [LDLR p.Pro685Arg](/variant/ldlr-p-pro685arg), [LDLR p.Pro685Ala](/variant/ldlr-p-pro685ala), [LDLR c.1186+5G>A](/variant/ldlr-c-1186-plus-5g-a).

### 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 252194). 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.*