# NM_031299.7(CDCA3):c.554G>A (p.Arg185His)

https://sugi.bio/variant/cdca3-p-arg185his

## Summary

**CDCA3 p.Arg185His (c.554G>A)** is classified **Uncertain significance** in CDCA3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-11). AlphaMissense: likely benign (0.08); Very rare (popmax 0.00115%, sas).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely benign · very rare (popmax 0.00115%, sas)

## For patients & families {#patients}

This is a change in the CDCA3 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 | [CDCA3](https://sugi.bio/atlas/gene/CDCA3/) |
| Protein change (HGVS p.) | p.Arg185His |
| Coding change (HGVS c.) | c.554G>A |
| MANE Select transcript | [NM_031299](https://www.ncbi.nlm.nih.gov/nuccore/NM_031299) |
| Variant type | single nucleotide variant |
| Location | chr12:6849420-6849420 (GRCh38) |
| ClinVar | [VCV3488567](https://www.ncbi.nlm.nih.gov/clinvar/variation/3488567/) |

**All HGVS expressions:** `NC_000012.11:g.6958584C>T`, `NC_000012.12:g.6849420C>T`, `NM_001297602.3:c.479G>A`, `NM_001297603.3:c.544+145G>A`, `NM_001297604.3:c.544+145G>A`, `NM_001331019.2:c.313+145G>A`, `NM_031299.7:c.554G>A`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.08)
- REVEL 0.003 (strongly benign-leaning) — agrees with AlphaMissense
- SaProt LLR -8.259 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP -4.788, GERP -5.08 — fast-evolving / accelerated position
- CADD: **PHRED 11.56**. 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 0.89** across the covering region of the MANE Select transcript (6,849,046–6,850,952), spanning 1,906 bp. Chi-square p 0.045. 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>G, Δ0.39 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 **0.00115%** (sas) · FAF95 0.000125% · FAF99 9.1e-05% · 1/87,162 in the highest group · 8/1,438,144 alleles overall — very rare (popmax 0.00115%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.00325% | 30,733 |
| South Asian (grpmax) | 0.00115% | 87,162 |
| European (non-Finnish) | 0.000428% | 233,634 |

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}

**CDCA3** population constraint: LOEUF 0.885, pLI 0.0038966, missense-Z 0.95067. *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 **185** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 59.01, 0% of residues very-high.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-10-11.

**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 | 2024-10-11 |

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

## Similar variants {#similar}

Related CDCA3 variant pages (same residue, condition, or type): [GNB3 p.Ala248Ser](/variant/gnb3-p-ala248ser), [GNB3 p.Ala248Thr](/variant/gnb3-p-ala248thr), [GNB3 p.Ala287Ser](/variant/gnb3-p-ala287ser), [GNB3 p.Arg251Cys](/variant/gnb3-p-arg251cys), [GNB3 p.Arg251His](/variant/gnb3-p-arg251his), [GNB3 p.Arg283Cys](/variant/gnb3-p-arg283cys), [GNB3 p.Arg283His](/variant/gnb3-p-arg283his), [GNB3 p.Arg304Cys](/variant/gnb3-p-arg304cys).

### 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 3488567). 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.*