# NM_006227.4(PLTP):c.561C>T (p.Val187=)

https://sugi.bio/variant/pltp-p-val187

## Summary

**PLTP p.Val187= (c.561C>T)** is classified **Benign** in PLTP (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-23). Low-frequency (popmax 1.55%, afr).

**At a glance:** Benign · review: Multiple submitters · rsID rs2229452 · 2 submitters · low-frequency (popmax 1.55%, afr)

## For patients & families {#patients}

This is a change in the PLTP gene that is classified as benign — not considered disease-causing, submitted by 2 submitters.

*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 | [PLTP](https://sugi.bio/atlas/gene/PLTP/) |
| Protein change (HGVS p.) | p.Val187= |
| Coding change (HGVS c.) | c.561C>T |
| MANE Select transcript | [NM_006227](https://www.ncbi.nlm.nih.gov/nuccore/NM_006227) |
| dbSNP | [rs2229452](https://www.ncbi.nlm.nih.gov/snp/rs2229452/) |
| Variant type | single nucleotide variant |
| Location | chr20:45907744-45907744 (GRCh38) |
| ClinVar | [VCV1600405](https://www.ncbi.nlm.nih.gov/clinvar/variation/1600405/) |

**All HGVS expressions:** `NC_000020.10:g.44536383G>A`, `NC_000020.11:g.45907744G>A`, `NG_012115.2:g.9404C>T`, `NM_001242920.2:c.276C>T`, `NM_001242921.1:c.297C>T`, `NM_006227.4:c.561C>T`, `NM_182676.3:c.405C>T`

## Computational & population evidence {#evidence}

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

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **acceptor gain** (Δ 0.30) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 0.183, GERP -3.27, phastCons 0.965 — weakly conserved position
- CADD: **PHRED 13.84**. 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.*
- SpliceAI deltas (raw): acceptor loss **0.01**, donor loss **0.00**, acceptor gain **0.30**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.01**, donor loss **0.00**, acceptor gain **0.30**, donor gain **0.00**.
- Pangolin: Δ**0.26** (gain), gain 0.26 / loss 0.12. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **1.55%** (afr) · FAF95 1.48% · FAF99 1.45% · 1,165/75,018 in the highest group · 1,292/1,613,762 alleles overall — low-frequency (popmax 1.55%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 1.55% | 64 |
| Remaining individuals (not grpmax-eligible) | 0.088% | 1,136 |
| Admixed American | 0.0817% | 1,224 |
| South Asian | 0.0022% | 45,435 |
| European (non-Finnish) | 0.00178% | 56,188 |

*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}

**PLTP** population constraint: LOEUF 1.002, pLI 2.8479e-12, missense-Z 0.88764. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 89.36, 71% of residues very-high.

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

*Describes the biological roles of PLTP (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:** PLTP's established molecular role includes high-density lipoprotein particle binding.


### Pathways affected {#pathways}

PLTP participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [HDL remodeling](https://reactome.org/content/detail/R-HSA-8964058) | other |
| [NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux](https://reactome.org/content/detail/R-HSA-9029569) | other |

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

**Molecular function:** high-density lipoprotein particle binding, phosphatidylethanolamine binding, diacylglycerol binding, low-density lipoprotein particle binding, phosphatidylcholine binding, very-low-density lipoprotein particle binding.

**Biological process:** lipid transport, positive regulation of cholesterol efflux, phospholipid transport, high-density lipoprotein particle remodeling, ceramide transport, glycolipid transport.

## Clinical significance {#significance}

**Benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-12-23.

**Submitter consensus:** unanimous (2/2 Benign).

**Submission history:** 2 submissions (2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2025-12-23 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related PLTP variant pages (same residue, condition, or type): [PLTP p.Ala155Thr](/variant/pltp-p-ala155thr), [PLTP p.Ala155Val](/variant/pltp-p-ala155val), [PLTP p.Arg177Cys](/variant/pltp-p-arg177cys), [PLTP p.Arg251Gln](/variant/pltp-p-arg251gln), [PLTP p.Arg372His](/variant/pltp-p-arg372his), [PLTP p.Arg380Gln](/variant/pltp-p-arg380gln), [PLTP p.Arg391Cys](/variant/pltp-p-arg391cys), [PLTP p.Arg394Pro](/variant/pltp-p-arg394pro).

### 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 1600405). 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.*