# NM_001321142.2(CIDEC):c.96G>T (p.Leu32=)

https://sugi.bio/variant/cidec-p-leu32

## Summary

**CIDEC p.Leu32= (c.96G>T)** is classified **Benign** in CIDEC (ClinVar, Multiple submitters, 5 submitters; last evaluated 2022-05-05). Common (popmax 46.7%, afr) — too common for a highly-penetrant pathogenic allele; Associated with CIDEC-related familial partial lipodystrophy.

**At a glance:** Benign · review: Multiple submitters · rsID rs456168 · 5 submitters · 1 linked condition · common (popmax 46.7%, afr) — too common for a highly-penetrant pathogenic allele

## For patients & families {#patients}

This is a change in the CIDEC gene that is classified as benign — not considered disease-causing, submitted by 5 submitters, and is linked to CIDEC-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 recessive |
| Age of onset (of this condition) | Adolescent |
| Prevalence | <1 / 1 000 000 (Worldwide) |

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

- Loss of subcutaneous adipose tissue in limbs — Obligate (100%)
- Lipodystrophy — Obligate (100%)
- Polycystic ovaries — Very frequent (99-80%)
- Insulin-resistant diabetes mellitus — Very frequent (99-80%)
- Oligomenorrhea — Very frequent (99-80%)
- Acanthosis nigricans — Very frequent (99-80%)
- Hepatic steatosis — Very frequent (99-80%)
- Pancreatitis — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0013125/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CIDEC](https://sugi.bio/atlas/gene/CIDEC/) |
| Protein change (HGVS p.) | p.Leu32= |
| Coding change (HGVS c.) | c.96G>T |
| MANE Select transcript | [NM_001321142](https://www.ncbi.nlm.nih.gov/nuccore/NM_001321142) |
| dbSNP | [rs456168](https://www.ncbi.nlm.nih.gov/snp/rs456168/) |
| Variant type | single nucleotide variant |
| Location | chr3:9877177-9877177 (GRCh38) |
| ClinVar | [VCV128774](https://www.ncbi.nlm.nih.gov/clinvar/variation/128774/) |

**All HGVS expressions:** `NC_000003.11:g.9918861C>A`, `NC_000003.12:g.9877177C>A`, `NG_042291.1:g.8078G>T`, `NM_001199551.2:c.96G>T`, `NM_001199552.2:c.96G>T`, `NM_001199623.1:c.135G>T`, `NM_001199623.2:c.135G>T`, `NM_001321142.2:c.96G>T`, `NM_001321143.2:c.-16+1257G>T`, `NM_001321144.2:c.-16+1257G>T`, `NM_001378491.1:c.96G>T`, `NM_022094.3:c.96G>T`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — common (popmax 46.7%, afr) — too common for a highly-penetrant pathogenic allele.

- **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 (below), not from a missing predictor score.
- Conservation: phyloP 2.054, GERP -0.88, phastCons 0.974 — highly conserved position (PP3-type support)
- CADD: **PHRED 8.474**. 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: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **46.7%** (afr) · FAF95 46.3% · FAF99 46.1% · 34,153/73,080 in the highest group · 347,934/1,550,738 alleles overall — common (popmax 46.7%, afr) — too common for a highly-penetrant pathogenic allele.

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 46.7% | 2 |
| Admixed American | 33.7% | 3 |
| Ashkenazi Jewish (not grpmax-eligible) | 24.5% | 4 |
| Finnish (not grpmax-eligible) | 24.4% | 4 |
| East Asian | 24.1% | 4 |
| South Asian | 23.7% | 4 |
| Remaining individuals (not grpmax-eligible) | 22.7% | 4 |
| Amish (not grpmax-eligible) | 21.9% | 5 |
| Middle Eastern | 21.6% | 5 |
| European (non-Finnish) | 20.1% | 5 |

*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}

**CIDEC** population constraint: LOEUF 0.927, pLI 0.0038824, missense-Z -0.064995; ClinGen dosage — haploinsufficiency 30, triplosensitivity 0 (0–3 scale). *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):

- **CIDEC-related familial partial lipodystrophy** — Moderate (AR)

## Protein context {#protein}

Residue **32** lies in the 'required for liquid-liquid phase separation (llps)' region.

AlphaFold model confidence (whole protein): pLDDT 74.19, 26% of residues very-high.

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

*Describes the biological roles of CIDEC (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}

CIDEC participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Lipid particle organization](https://reactome.org/content/detail/R-HSA-8964572) | curated |
| [Assembly of active LPL and LIPC lipase complexes](https://reactome.org/content/detail/R-HSA-8963889) | other |
| [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}

**Biological process:** apoptotic process, lipid storage, lipid droplet organization, negative regulation of lipid catabolic process, execution phase of apoptosis, lipid droplet fusion.

## Clinical significance {#significance}

**Benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2022-05-05.

**Submitter consensus:** conflicting (4 Benign, 1 Likely benign).

**Submission history:** 5 submissions (2021–2022); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Genetic Services Laboratory, University of Chicago | Likely benign | no assertion criteria provided | clinical testing |  |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2021-06-09 |
| Mayo Clinic Laboratories, Mayo Clinic | Benign | criteria provided, single submitter | clinical testing | 2022-05-05 |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |
| Genome-Nilou Lab | Benign | criteria provided, single submitter | clinical testing | 2021-07-22 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** CIDEC-related familial partial lipodystrophy, not specified, not provided, LIPODYSTROPHY, FAMILIAL PARTIAL, ASSOCIATED WITH CIDEC MUTATIONS, Familial partial lipodystrophy 5, AllHighlyPenetrant, none provided.

## Similar variants {#similar}

Related CIDEC variant pages (same residue, condition, or type): [CIDEC p.Glu186Ter](/variant/cidec-p-glu186ter), [CIDEC p.Gln211fs](/variant/cidec-p-gln211fs), [CIDEC p.Gly204fs](/variant/cidec-p-gly204fs), [CIDEC p.Lys223fs](/variant/cidec-p-lys223fs), [CIDEC p.Arg182His](/variant/cidec-p-arg182his), [CIDEC p.Ile156Thr](/variant/cidec-p-ile156thr), [CIDEC p.Met195Ile](/variant/cidec-p-met195ile), [CIDEC p.Val54Met](/variant/cidec-p-val54met).

### 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 128774). 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.*