# NM_020661.4(AICDA):c.259T>C (p.Cys87Arg)

https://sugi.bio/variant/aicda-p-cys87arg

## Summary

**AICDA p.Cys87Arg (c.259T>C)** is classified **Pathogenic/Likely pathogenic** in AICDA (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-03-17). AlphaMissense: likely pathogenic (0.9887); Very rare (popmax 0.00127%, nfe); Associated with hyper-IgM syndrome type 2.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs762590894 · 5 submitters · 1 linked condition · AlphaMissense likely pathogenic · very rare (popmax 0.00127%, nfe)

## For patients & families {#patients}

This is a change in the AICDA gene that is considered likely disease-causing, submitted by 5 submitters, and is linked to hyper-IgM syndrome type 2.

*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:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0010578/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [AICDA](https://sugi.bio/atlas/gene/AICDA/) |
| Protein change (HGVS p.) | p.Cys87Arg |
| Coding change (HGVS c.) | c.259T>C |
| MANE Select transcript | [NM_020661](https://www.ncbi.nlm.nih.gov/nuccore/NM_020661) |
| dbSNP | [rs762590894](https://www.ncbi.nlm.nih.gov/snp/rs762590894/) |
| Variant type | single nucleotide variant |
| Location | chr12:8605383-8605383 (GRCh38) |
| ClinVar | [VCV617969](https://www.ncbi.nlm.nih.gov/clinvar/variation/617969/) |

**All HGVS expressions:** `LRG_17:g.12464T>C`, `LRG_17t1:c.259T>C`, `NC_000012.11:g.8757979A>G`, `NC_000012.12:g.8605383A>G`, `NG_011588.1:g.12464T>C`, `NM_001330343.2:c.259T>C`, `NM_020661.4:c.259T>C`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- AlphaMissense **likely pathogenic** (0.9887) — concordant with the pathogenic call
- REVEL 0.978 (strongly pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -6.01 (tolerated) — differs from AlphaMissense
- → **In-silico consensus:** AlphaMissense and REVEL call this damaging; SaProt does not
- Conservation: phyloP 11.108, GERP 1.72, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 5%** most-pathogenic-predicted substitutions in AICDA (of 1,154 modeled).
- CADD: **PHRED 29.6**. 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 (8,604,287–8,612,767), spanning 8,480 bp. Chi-square p 0.018. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code 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 **0.00127%** (nfe) · FAF95 0.000763% · FAF99 0.000605% · 15/1,180,042 in the highest group · 16/1,614,110 alleles overall — very rare (popmax 0.00127%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Finnish (not grpmax-eligible) | 0.00156% | 64,040 |
| European (non-Finnish) (grpmax) | 0.00127% | 78,670 |

Finnish 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}

**AICDA** population constraint: LOEUF 1.144, pLI 1.2839e-05, missense-Z 0.99122; ClinGen dosage — haploinsufficiency 30, triplosensitivity Not yet evaluated (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):

- **hyper-IgM syndrome type 2** — Definitive (AR)
- **hyper-IgM syndrome type 2** — Definitive (AD)

## Protein context {#protein}

Residue **87** lies in the cmp/dcmp-type deaminase domain; a UniProt-annotated variant site (in higm2; uncertain significance); an α-helix; a binding site.

AlphaFold model confidence (whole protein): pLDDT 88.43, 73% of residues very-high.

**5 experimental structure(s)** (PDB): [5JJ4](https://www.rcsb.org/structure/5JJ4), [5W0R](https://www.rcsb.org/structure/5W0R), [5W0U](https://www.rcsb.org/structure/5W0U), [5W0Z](https://www.rcsb.org/structure/5W0Z), [5W1C](https://www.rcsb.org/structure/5W1C) — incl. mutant structure 5JJ4.

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

*Describes the biological roles of AICDA (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:** AICDA's established molecular role includes cytidine deaminase activity. p.Cys87Arg falls in the cmp/dcmp-type deaminase domain.


### Pathways affected {#pathways}

AICDA participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Chromatin modifications during the maternal to zygotic transition (MZT)](https://reactome.org/content/detail/R-HSA-9821002) | electronic |
| [Somatic hypermutation of immunoglobulin genes](https://reactome.org/content/detail/R-HSA-9938024) | electronic |

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

**Molecular function:** cytidine deaminase activity, ubiquitin protein ligase binding, identical protein binding.

**Biological process:** somatic diversification of immunoglobulins, somatic hypermutation of immunoglobulin genes, regulation of nuclear cell cycle DNA replication, positive regulation of gene expression via chromosomal CpG island demethylation.

## Clinical significance {#significance}

**Pathogenic/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-03-17.

**Submitter consensus:** conflicting (4 Pathogenic, 1 Likely pathogenic).

**Submission history:** 5 submissions (2018–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Pathogenic | criteria provided, single submitter | clinical testing | 2018-02-06 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2026-01-05 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Pathogenic | criteria provided, single submitter | clinical testing | 2024-10-18 |
| Revvity Omics, Revvity | Pathogenic | criteria provided, single submitter | clinical testing | 2024-09-04 |
| GeneDx | Likely pathogenic | criteria provided, single submitter | clinical testing | 2026-03-17 |

## Associated conditions {#conditions}

[hyper-IgM syndrome type 2](https://sugi.bio/atlas/disease/hyper-igm-syndrome-type-2/).

**Reported phenotype names (ClinVar):** Hyper-IgM syndrome type 2, not provided, none provided, Hyper-IgM Immunodeficiency Syndrome, Type 2.

## Same-residue context {#hotspot}

Residue **87** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [AICDA p.Cys87Ser](/variant/aicda-p-cys87ser). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related AICDA variant pages (same residue, condition, or type): [AICDA p.Cys87Ser](/variant/aicda-p-cys87ser), [AICDA p.Cys87Gly](/variant/aicda-p-cys87gly), [AICDA p.Arg112Cys](/variant/aicda-p-arg112cys), [AICDA p.Arg190Ter](/variant/aicda-p-arg190ter), [AICDA p.Arg24Trp](/variant/aicda-p-arg24trp), [AICDA p.Arg92Ter](/variant/aicda-p-arg92ter), [AICDA p.Arg99Ter](/variant/aicda-p-arg99ter), [AICDA p.Cys147Ter](/variant/aicda-p-cys147ter).

### 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 617969). 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.*