# NM_002666.5(PLIN1):c.691C>T (p.Arg231Ter)

https://sugi.bio/variant/plin1-p-arg231ter

## Summary

**PLIN1 p.Arg231Ter (c.691C>T)** is classified **Uncertain significance** in PLIN1 (ClinVar, Single submitter, 1 submitter). Very rare (popmax 0.004%, afr); Associated with PLIN1-related familial partial lipodystrophy.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs974117029 · 1 submitter · 1 linked condition · very rare (popmax 0.004%, afr)

## For patients & families {#patients}

This is a change in the PLIN1 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to PLIN1-related familial partial lipodystrophy.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant |
| Age of onset (of this condition) | Childhood |
| Diagnostic panels | PLIN1 is a diagnostic-grade gene on 3 Genomics England panels |

**Commonly reported features of PLIN1-related familial partial lipodystrophy** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Hypertension — Obligate (100%)
- Hyperinsulinemia — Obligate (100%)
- Insulin-resistant diabetes mellitus at puberty — Obligate (100%)
- Acanthosis nigricans — Obligate (100%)
- Hepatic steatosis — Obligate (100%)
- Hypertriglyceridemia — Obligate (100%)
- Lipoatrophy — Obligate (100%)
- Infertility — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0012601/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [PLIN1](https://sugi.bio/atlas/gene/PLIN1/) |
| Protein change (HGVS p.) | p.Arg231Ter |
| Coding change (HGVS c.) | c.691C>T |
| MANE Select transcript | [NM_002666](https://www.ncbi.nlm.nih.gov/nuccore/NM_002666) |
| dbSNP | [rs974117029](https://www.ncbi.nlm.nih.gov/snp/rs974117029/) |
| Variant type | single nucleotide variant |
| Location | chr15:89669580-89669580 (GRCh38) |
| ClinVar | [VCV1339162](https://www.ncbi.nlm.nih.gov/clinvar/variation/1339162/) |

**All HGVS expressions:** `NC_000015.10:g.89669580G>A`, `NC_000015.9:g.90212811G>A`, `NG_029172.1:g.14838C>T`, `NM_001145311.2:c.691C>T`, `NM_002666.4:c.691C>T`, `NM_002666.5:c.691C>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 0.31) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 4.132, GERP 0.361, phastCons 0.867 — highly conserved position (PP3-type support)
- Molecular consequence: **nonsense (stop-gain)** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.201, pLI 3.4483e-12. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 6 of 9**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 36.0**. 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.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.31**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.31**, donor gain **0.00**.
- Population frequency (gnomAD v4.1): grpmax **0.004%** (afr) · FAF95 0.00106% · FAF99 0.000495% · 3/74,920 in the highest group · 8/1,613,858 alleles overall — very rare (popmax 0.004%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.004% | 24,973 |
| East Asian | 0.00223% | 44,882 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,480 |
| European (non-Finnish) | 0.000254% | 393,312 |

*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}

**PLIN1** population constraint: LOEUF 1.201, pLI 3.4483e-12, missense-Z -2.213. *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):

- **PLIN1-related familial partial lipodystrophy** — Definitive (AD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 54.52, 0% of residues very-high.

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

*Describes the biological roles of PLIN1 (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.*


### Pathways affected {#pathways}

PLIN1 participates in **4 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [NR1H2 & NR1H3 regulate gene expression linked to triglyceride lipolysis in adipose](https://reactome.org/content/detail/R-HSA-9031528) | 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 |
| [Triglyceride catabolism](https://reactome.org/content/detail/R-HSA-163560) | electronic |

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Neuberg Centre For Genomic Medicine, NCGM | Uncertain significance | criteria provided, single submitter | clinical testing |  |

## Associated conditions {#conditions}

[PLIN1-related familial partial lipodystrophy](https://sugi.bio/atlas/disease/plin1-related-familial-partial-lipodystrophy/).

**Reported phenotype names (ClinVar):** PLIN1-related familial partial lipodystrophy, LIPODYSTROPHY, FAMILIAL PARTIAL, ASSOCIATED WITH PLIN1 MUTATIONS.

## Similar variants {#similar}

Related PLIN1 variant pages (same residue, condition, or type): [PLIN1 p.Arg231Leu](/variant/plin1-p-arg231leu), [PLIN1 p.Leu90Pro](/variant/plin1-p-leu90pro), [PLIN1 p.Thr345Ala](/variant/plin1-p-thr345ala), [PLIN1 c.772-23T>A](/variant/plin1-c-772-minus-23t-a), [PLIN1 p.Pro194Ala](/variant/plin1-p-pro194ala), [PLIN1 p.Pro371=](/variant/plin1-p-pro371), [PLIN1 p.Val373=](/variant/plin1-p-val373), [PLIN1 p.Arg93Ter](/variant/plin1-p-arg93ter).

### 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 2026-07-14); 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 1339162). 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.*