# NM_001290474.2(C2CD2L):c.1155C>G (p.Cys385Trp)

https://sugi.bio/variant/c2cd2l-p-cys385trp

## Summary

**C2CD2L p.Cys385Trp (c.1155C>G)** is classified **Uncertain significance** in C2CD2L (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-15). AlphaMissense: ambiguous (0.3605); Very rare (popmax 0.00668%, eas).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense ambiguous · very rare (popmax 0.00668%, eas)

## For patients & families {#patients}

This is a change in the C2CD2L gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter.

*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 | [C2CD2L](https://sugi.bio/atlas/gene/C2CD2L/) |
| Protein change (HGVS p.) | p.Cys385Trp |
| Coding change (HGVS c.) | c.1155C>G |
| MANE Select transcript | [NM_001290474](https://www.ncbi.nlm.nih.gov/nuccore/NM_001290474) |
| Variant type | single nucleotide variant |
| Location | chr11:119112552-119112552 (GRCh38) |
| ClinVar | [VCV4217227](https://www.ncbi.nlm.nih.gov/clinvar/variation/4217227/) |

**All HGVS expressions:** `NC_000011.10:g.119112552C>G`, `NC_000011.9:g.118983262C>G`, `NM_001290474.2:c.1155C>G`, `NM_001382611.1:c.1044C>G`, `NM_001382612.1:c.1155C>G`, `NM_001382613.1:c.1155C>G`, `NM_014807.5:c.1155C>G`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense makes no call; REVEL and SaProt both call this tolerated; AlphaMissense makes no call — descriptive only.

- AlphaMissense **ambiguous** (0.3605) — no call either way
- REVEL 0.202 (benign-leaning)
- SaProt LLR -8.039 (tolerated)
- → **In-silico consensus:** REVEL and SaProt both call this tolerated; AlphaMissense makes no call
- Conservation: phyloP 0.197, GERP -1.35, phastCons 0.972 — weakly conserved position
- CADD: **PHRED 21.7**. 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 0.86** across the covering region of the MANE Select transcript (119,107,742–119,116,253), spanning 8,511 bp. Chi-square p 2.1e-05. 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 (C>T, Δ0.20 acceptor 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 **0.00668%** (eas) · FAF95 0.00177% · FAF99 0.000891% · 3/44,878 in the highest group · 3/1,460,920 alleles overall — very rare (popmax 0.00668%, eas).

*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}

**C2CD2L** population constraint: LOEUF 0.494, pLI 0.98316, missense-Z 1.5329. *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 **385** lies in the c2 domain.

AlphaFold model confidence (whole protein): pLDDT 64.75, 17% of residues very-high.

**1 experimental structure(s)** (PDB): [5TOD](https://www.rcsb.org/structure/5TOD).

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

*Describes the biological roles of C2CD2L (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:** C2CD2L's established molecular role includes phosphatidylinositol transfer activity. p.Cys385Trp falls in the c2 domain.


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

**Molecular function:** phosphatidylinositol transfer activity, phosphatidylinositol binding.

**Biological process:** positive regulation of insulin secretion involved in cellular response to glucose stimulus.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-07-15.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-07-15 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related C2CD2L variant pages (same residue, condition, or type): [C2CD2L c.451-8G>A](/variant/c2cd2l-c-451-minus-8g-a), [C2CD2L p.Ala14Thr](/variant/c2cd2l-p-ala14thr), [C2CD2L p.Ala173Thr](/variant/c2cd2l-p-ala173thr), [C2CD2L p.Ala245Ser](/variant/c2cd2l-p-ala245ser), [C2CD2L p.Ala245Thr](/variant/c2cd2l-p-ala245thr), [C2CD2L p.Ala326Val](/variant/c2cd2l-p-ala326val), [C2CD2L p.Ala512Val](/variant/c2cd2l-p-ala512val), [C2CD2L p.Ala524Thr](/variant/c2cd2l-p-ala524thr).

### 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 4217227). 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.*