# NM_005831.5(CALCOCO2):c.541C>G (p.Gln181Glu)

https://sugi.bio/variant/calcoco2-p-gln181glu

## Summary

**CALCOCO2 p.Gln181Glu (c.541C>G)** is classified **Uncertain significance** in CALCOCO2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-20). AlphaMissense: likely benign (0.0694); Very rare (popmax 0.00167%, amr).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely benign · very rare (popmax 0.00167%, amr)

## For patients & families {#patients}

This is a change in the CALCOCO2 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 | [CALCOCO2](https://sugi.bio/atlas/gene/CALCOCO2/) |
| Protein change (HGVS p.) | p.Gln181Glu |
| Coding change (HGVS c.) | c.541C>G |
| MANE Select transcript | [NM_005831](https://www.ncbi.nlm.nih.gov/nuccore/NM_005831) |
| Variant type | single nucleotide variant |
| Location | chr17:48849375-48849375 (GRCh38) |
| ClinVar | [VCV4647751](https://www.ncbi.nlm.nih.gov/clinvar/variation/4647751/) |

**All HGVS expressions:** `NC_000017.10:g.46926737C>G`, `NC_000017.11:g.48849375C>G`, `NM_001261390.2:c.613C>G`, `NM_001261391.2:c.604C>G`, `NM_001261393.2:c.417+920C>G`, `NM_001261395.2:c.325C>G`, `NM_005831.5:c.541C>G`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.0694)
- REVEL 0.043 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -6.237 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 5.083, GERP 1.39, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 19.81**. 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 1.05** across the covering region of the MANE Select transcript (48,848,076–48,852,599), spanning 4,523 bp. Chi-square p 0.48. 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, Δ0.99 donor 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 **0.00167%** (amr) · 1/59,980 in the highest group · 4/1,460,440 alleles overall — very rare (popmax 0.00167%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.00321% | 31,200 |
| Admixed American (grpmax) | 0.00167% | 59,980 |
| European (non-Finnish) | 8.48e-05% | 1,179,585 |

Remaining individuals shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}

**CALCOCO2** population constraint: LOEUF 0.933, pLI 0.00019635, missense-Z 1.0594. *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 81.16, 56% of residues very-high.

**10 experimental structure(s)** (PDB): [2MXP](https://www.rcsb.org/structure/2MXP), [3VVV](https://www.rcsb.org/structure/3VVV), [3VVW](https://www.rcsb.org/structure/3VVW), [4GXL](https://www.rcsb.org/structure/4GXL), [4HAN](https://www.rcsb.org/structure/4HAN), [4XKL](https://www.rcsb.org/structure/4XKL).

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

*Describes the biological roles of CALCOCO2 (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:** CALCOCO2's established molecular role includes protein homodimerization activity.


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

**Molecular function:** protein homodimerization activity.

**Biological process:** response to type II interferon, xenophagy, positive regulation of autophagosome maturation.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-11-20.

**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 | 2025-11-20 |

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

## Similar variants {#similar}

Related CALCOCO2 variant pages (same residue, condition, or type): [CALCOCO2 p.Gln181Lys](/variant/calcoco2-p-gln181lys), [CALCOCO2 p.His267Arg](/variant/calcoco2-p-his267arg), [CALCOCO2 p.Ala175Val](/variant/calcoco2-p-ala175val), [CALCOCO2 p.Ala323Asp](/variant/calcoco2-p-ala323asp), [CALCOCO2 p.Ala375Thr](/variant/calcoco2-p-ala375thr), [CALCOCO2 p.Arg117Gln](/variant/calcoco2-p-arg117gln), [CALCOCO2 p.Arg117Trp](/variant/calcoco2-p-arg117trp), [CALCOCO2 p.Arg126Cys](/variant/calcoco2-p-arg126cys).

### 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 4647751). 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.*