# NM_006227.4(PLTP):c.1181G>C (p.Arg394Pro)

https://sugi.bio/variant/pltp-p-arg394pro

## Summary

**PLTP p.Arg394Pro (c.1181G>C)** is classified **Uncertain significance** in PLTP (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-05-12). AlphaMissense: likely pathogenic (0.8249); Very rare (popmax 0.00259%, amr).

**At a glance:** Uncertain significance · review: Multiple submitters · 2 submitters · AlphaMissense likely pathogenic · very rare (popmax 0.00259%, amr)

## For patients & families {#patients}

This is a change in the PLTP gene that is currently of uncertain significance — a definitive interpretation has not yet been established, 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.Arg394Pro |
| Coding change (HGVS c.) | c.1181G>C |
| MANE Select transcript | [NM_006227](https://www.ncbi.nlm.nih.gov/nuccore/NM_006227) |
| Variant type | single nucleotide variant |
| Location | chr20:45899873-45899873 (GRCh38) |
| ClinVar | [VCV3307872](https://www.ncbi.nlm.nih.gov/clinvar/variation/3307872/) |

**All HGVS expressions:** `NC_000020.10:g.44528512C>G`, `NC_000020.11:g.45899873C>G`, `NG_008291.1:g.13922C>G`, `NG_012115.2:g.17275G>C`, `NM_001242920.2:c.896G>C`, `NM_001242921.1:c.917G>C`, `NM_006227.4:c.1181G>C`, `NM_182676.3:c.1025G>C`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.8249)
- REVEL 0.168 (moderately benign-leaning) — differs from AlphaMissense
- SaProt LLR -12.39 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt call this damaging; REVEL does not
- SpliceAI predicts **donor loss** (Δ 0.24) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 5.956, GERP 0.034, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 28.0**. 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 0.94** across the covering region of the MANE Select transcript (45,898,944–45,911,452), spanning 12,508 bp. Chi-square p 0.099. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.16**, donor loss **0.24**, acceptor gain **0.00**, donor gain **0.00**. Largest is donor loss.
- SpliceAI deltas (masked): acceptor loss **0.16**, donor loss **0.24**, acceptor gain **0.00**, donor gain **0.00**.
- Population frequency (gnomAD v4.1): grpmax **0.00259%** (amr) · 1/38,540 in the highest group · 1/118,730 alleles overall — very rare (popmax 0.00259%, amr).

*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}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-05-12.

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

**Submission history:** 2 submissions (2024); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-05-12 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-01-30 |

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

## Similar variants {#similar}

Related PLTP variant pages (same residue, condition, or type): [PLTP p.Arg394Ter](/variant/pltp-p-arg394ter), [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).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 2026-10-14); 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 3307872). 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.*