# NM_000237.3(LPL):c.1385T>C (p.Phe462Ser)

https://sugi.bio/variant/lpl-p-phe462ser

## Summary

**LPL p.Phe462Ser (c.1385T>C)** is classified **Uncertain significance** in LPL (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-12-08). AlphaMissense: likely pathogenic (0.9917); Very rare (popmax 0.00167%, amr); Associated with Cardiovascular phenotype.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs776532284 · 2 submitters · 1 linked condition · AlphaMissense likely pathogenic · very rare (popmax 0.00167%, amr)

## For patients & families {#patients}

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

*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.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [LPL](https://sugi.bio/atlas/gene/LPL/) |
| Protein change (HGVS p.) | p.Phe462Ser |
| Coding change (HGVS c.) | c.1385T>C |
| MANE Select transcript | [NM_000237](https://www.ncbi.nlm.nih.gov/nuccore/NM_000237) |
| dbSNP | [rs776532284](https://www.ncbi.nlm.nih.gov/snp/rs776532284/) |
| Variant type | single nucleotide variant |
| Location | chr8:19962177-19962177 (GRCh38) |
| ClinVar | [VCV1771384](https://www.ncbi.nlm.nih.gov/clinvar/variation/1771384/) |

**All HGVS expressions:** `LRG_1298:g.65461T>C`, `LRG_1298t1:c.1385T>C`, `NC_000008.10:g.19819688T>C`, `NC_000008.11:g.19962177T>C`, `NG_008855.2:g.65461T>C`, `NM_000237.3:c.1385T>C`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **damaging** — a triage signal, not a reclassification.

- AlphaMissense **likely pathogenic** (0.9917)
- REVEL 0.735 (pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -14.217 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 7.875, GERP 2.43, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 8%** most-pathogenic-predicted substitutions in LPL (of 2,786 modeled).
- CADD: **PHRED 27.0**. 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 1.09** across the covering region of the MANE Select transcript (19,939,441–19,962,217), spanning 22,776 bp. Chi-square p 0.027. 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 (T>G, Δ0.76 donor gain), 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 (gnomAD v4.1): grpmax **0.00167%** (amr) · FAF95 7.9e-05% · FAF99 5.4e-05% · 1/59,994 in the highest group · 6/1,613,776 alleles overall — very rare (popmax 0.00167%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.00167% | 59,994 |
| South Asian | 0.0011% | 91,082 |
| European (non-Finnish) | 0.000339% | 294,957 |

*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}

**LPL** population constraint: LOEUF 1.075, pLI 3.1242e-12, missense-Z -0.35897. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **462** lies in a β-strand; the plat domain; a disulfide bond; the 'interaction with gpihbp1' region.

AlphaFold model confidence (whole protein): pLDDT 91.36, 82% of residues very-high.

**5 experimental structure(s)** (PDB): [6E7K](https://www.rcsb.org/structure/6E7K), [6OAU](https://www.rcsb.org/structure/6OAU), [6OAZ](https://www.rcsb.org/structure/6OAZ), [6OB0](https://www.rcsb.org/structure/6OB0), [6WN4](https://www.rcsb.org/structure/6WN4) — incl. mutant structure 6OAU.

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

*Describes the biological roles of LPL (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:** LPL's established molecular role includes lipoprotein lipase activity. p.Phe462Ser falls in the plat domain.


### Pathways affected {#pathways}

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

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Assembly of active LPL and LIPC lipase complexes](https://reactome.org/content/detail/R-HSA-8963889) | curated |
| [Chylomicron remodeling](https://reactome.org/content/detail/R-HSA-8963901) | curated |
| [Retinoid metabolism and transport](https://reactome.org/content/detail/R-HSA-975634) | curated |
| [Transcriptional regulation of white adipocyte differentiation](https://reactome.org/content/detail/R-HSA-381340) | curated |
| [MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis](https://reactome.org/content/detail/R-HSA-9841922) | electronic |

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

**Molecular function:** lipoprotein lipase activity, triacylglycerol lipase activity, signaling receptor binding, calcium ion binding, heparin binding, glycerophospholipid phospholipase A1 activity.

**Biological process:** fatty acid metabolic process, fatty acid biosynthetic process, triglyceride metabolic process, positive regulation of macrophage derived foam cell differentiation, positive regulation of cholesterol storage, triglyceride catabolic process.

## Clinical significance {#significance}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2023-12-08.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2021–2023); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-06-30 |
| Mayo Clinic Laboratories, Mayo Clinic | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-12-08 |

## Associated conditions {#conditions}

[Cardiovascular phenotype](https://sugi.bio/atlas/disease/cardiovascular-phenotype/).

**Reported phenotype names (ClinVar):** Cardiovascular phenotype, not provided, none provided, RECLASSIFIED - ADRA2C POLYMORPHISM, RECLASSIFIED - ADRB1 POLYMORPHISM.

## Similar variants {#similar}

Related LPL variant pages (same residue, condition, or type): [LPL c.1019-2A>T](/variant/lpl-c-1019-minus-2a-t), [LPL c.1139+1G>A](/variant/lpl-c-1139-plus-1g-a), [LPL c.1322+1G>C](/variant/lpl-c-1322-plus-1g-c), [LPL c.249+1G>A](/variant/lpl-c-249-plus-1g-a), [LPL p.Ala98Thr](/variant/lpl-p-ala98thr), [LPL p.Arg197Cys](/variant/lpl-p-arg197cys), [LPL p.Asp277Asn](/variant/lpl-p-asp277asn), [LPL p.Gln133Ter](/variant/lpl-p-gln133ter).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); 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 2026-07-14); 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 1771384). 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.*