# NM_152562.4(CDCA2):c.829G>T (p.Val277Phe)

https://sugi.bio/variant/cdca2-p-val277phe

## Summary

**CDCA2 p.Val277Phe (c.829G>T)** is classified **Uncertain significance** in CDCA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-29). AlphaMissense: likely benign (0.1079); Very rare (popmax 0.005%, amr).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs1252270949 · 1 submitter · AlphaMissense likely benign · very rare (popmax 0.005%, amr)

## For patients & families {#patients}

This is a change in the CDCA2 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 | [CDCA2](https://sugi.bio/atlas/gene/CDCA2/) |
| Protein change (HGVS p.) | p.Val277Phe |
| Coding change (HGVS c.) | c.829G>T |
| MANE Select transcript | [NM_152562](https://www.ncbi.nlm.nih.gov/nuccore/NM_152562) |
| dbSNP | [rs1252270949](https://www.ncbi.nlm.nih.gov/snp/rs1252270949/) |
| Variant type | single nucleotide variant |
| Location | chr8:25479921-25479921 (GRCh38) |
| ClinVar | [VCV2314549](https://www.ncbi.nlm.nih.gov/clinvar/variation/2314549/) |

**All HGVS expressions:** `NC_000008.10:g.25337437G>T`, `NC_000008.11:g.25479921G>T`, `NG_084831.1:g.850G>T`, `NM_001317906.1:c.784G>T`, `NM_001317907.1:c.829G>T`, `NM_152562.4:c.829G>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.1079)
- REVEL 0.074 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -7.755 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- SpliceAI predicts **acceptor loss** (Δ 0.23) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 1.289, GERP -1.49, phastCons 0.001 — weakly conserved position
- CADD: **PHRED 9.849**. 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 1.04** across the covering region of the MANE Select transcript (25,460,240–25,507,735), spanning 47,495 bp. Chi-square p 0.15. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.23**, donor loss **0.00**, acceptor gain **0.04**, donor gain **0.00**. Largest is acceptor loss, 8 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.04**, donor gain **0.00**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Population frequency (gnomAD v4.1): grpmax **0.005%** (amr) · FAF95 0.00133% · FAF99 0.000668% · 3/60,000 in the highest group · 7/1,614,012 alleles overall — very rare (popmax 0.005%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.005% | 20,000 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,484 |
| European (non-Finnish) | 0.000254% | 393,338 |

*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}

**CDCA2** population constraint: LOEUF 0.84, pLI 9.4051e-07, missense-Z 0.14446. *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 46.61, 1% of residues very-high.

**4 experimental structure(s)** (PDB): [5D1Z](https://www.rcsb.org/structure/5D1Z), [5INB](https://www.rcsb.org/structure/5INB), [5IOH](https://www.rcsb.org/structure/5IOH), [5SW9](https://www.rcsb.org/structure/5SW9).

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

*Describes the biological roles of CDCA2 (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:** CDCA2's established molecular role includes protein phosphatase regulator activity.


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

**Molecular function:** protein phosphatase regulator activity.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-09-29.

**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 | 2022-09-29 |

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

## Similar variants {#similar}

Related CDCA2 variant pages (same residue, condition, or type): [CDCA2 p.Val467Ile](/variant/cdca2-p-val467ile), [CDCA2 p.Lys754Thr](/variant/cdca2-p-lys754thr), [CDCA2 p.Ser291=](/variant/cdca2-p-ser291), [CDCA2 p.Thr50Ile](/variant/cdca2-p-thr50ile), [CDCA2 p.Ala187Thr](/variant/cdca2-p-ala187thr), [CDCA2 p.Ala217Val](/variant/cdca2-p-ala217val), [CDCA2 p.Ala23Val](/variant/cdca2-p-ala23val), [CDCA2 p.Ala92Gly](/variant/cdca2-p-ala92gly).

### 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 2314549). 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.*