# NM_031942.5(CDCA7):c.745A>C (p.Arg249=)

https://sugi.bio/variant/cdca7-p-arg249

## Summary

**CDCA7 p.Arg249= (c.745A>C)** is classified **Conflicting classifications of pathogenicity** in CDCA7 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-02-01). Rare (popmax 0.144%, nfe); Associated with immunodeficiency-centromeric instability-facial anomalies syndrome 3.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs146148251 · 5 submitters · 1 linked condition · rare (popmax 0.144%, nfe)

## For patients & families {#patients}

This is a change in the CDCA7 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 5 submitters, and is linked to immunodeficiency-centromeric instability-facial anomalies syndrome 3.

*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/0016168/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CDCA7](https://sugi.bio/atlas/gene/CDCA7/) |
| Protein change (HGVS p.) | p.Arg249= |
| Coding change (HGVS c.) | c.745A>C |
| MANE Select transcript | [NM_031942](https://www.ncbi.nlm.nih.gov/nuccore/NM_031942) |
| dbSNP | [rs146148251](https://www.ncbi.nlm.nih.gov/snp/rs146148251/) |
| Variant type | single nucleotide variant |
| Location | chr2:173364840-173364840 (GRCh38) |
| ClinVar | [VCV707884](https://www.ncbi.nlm.nih.gov/clinvar/variation/707884/) |

**All HGVS expressions:** `NC_000002.11:g.174229568A>C`, `NC_000002.12:g.173364840A>C`, `NG_047202.1:g.15824A>C`, `NM_031942.5:c.745A>C`, `NM_145810.3:c.508A>C`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **acceptor loss** (Δ 0.26) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 2.367, GERP 0.381, phastCons 0.683 — highly conserved position (PP3-type support)
- CADD: **PHRED 12.21**. 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.*
- SpliceAI deltas (raw): acceptor loss **0.26**, donor loss **0.00**, acceptor gain **0.05**, donor gain **0.00**. Largest is acceptor loss, 2 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.05**, 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 **0.144%** (nfe) · FAF95 0.138% · FAF99 0.136% · 1,699/1,179,156 in the highest group · 1,741/1,611,396 alleles overall — rare (popmax 0.144%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.144% | 694 |
| Remaining individuals (not grpmax-eligible) | 0.0481% | 2,080 |
| African / African-American | 0.0134% | 7,482 |
| Finnish (not grpmax-eligible) | 0.00312% | 32,014 |

*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}

**CDCA7** population constraint: LOEUF 0.676, pLI 0.002565, missense-Z 1.8093. *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):

- **immunodeficiency-centromeric instability-facial anomalies syndrome 3** — Moderate (AR)

## Protein context {#protein}

Residue **249** lies in an α-helix.

AlphaFold model confidence (whole protein): pLDDT 68.93, 33% of residues very-high.

**2 experimental structure(s)** (PDB): [8TLK](https://www.rcsb.org/structure/8TLK), [8YV8](https://www.rcsb.org/structure/8YV8).

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

*Describes the biological roles of CDCA7 (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:** CDCA7's established molecular role includes hemi-methylated DNA-binding.


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

**Molecular function:** hemi-methylated DNA-binding.

**Biological process:** regulation of cell population proliferation.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2026-02-01.

**Submitter consensus:** conflicting (4 Likely benign, 1 Uncertain significance).

**Submission history:** 5 submissions (2019–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Likely benign | criteria provided, single submitter | clinical testing | 2023-11-29 |
| Breakthrough Genomics, Breakthrough Genomics | Likely benign | criteria provided, single submitter | not provided |  |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2019-03-04 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-02-01 |
| Blueprint Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-11-22 |

## Associated conditions {#conditions}

[immunodeficiency-centromeric instability-facial anomalies syndrome 3](https://sugi.bio/atlas/disease/immunodeficiency-centromeric-instability-facial-anomalies-syndrome-3/).

**Reported phenotype names (ClinVar):** Immunodeficiency-centromeric instability-facial anomalies syndrome 3, not provided, CDCA7-related disorder, none provided, CDCA7-related condition.

## Similar variants {#similar}

Related CDCA7 variant pages (same residue, condition, or type): [CDCA7 p.Ala391Gly](/variant/cdca7-p-ala391gly), [CDCA7 p.Pro244Leu](/variant/cdca7-p-pro244leu), [CDCA7 c.22-17G>T](/variant/cdca7-c-22-minus-17g-t), [CDCA7 c.622-128C>T](/variant/cdca7-c-622-minus-128c-t), [CDCA7 c.895-27C>G](/variant/cdca7-c-895-minus-27c-g), [CDCA7 p.Asn331=](/variant/cdca7-p-asn331), [CDCA7 p.Thr359=](/variant/cdca7-p-thr359), [CDCA7 p.Arg353Cys](/variant/cdca7-p-arg353cys).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 2026-10-14); 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 707884). 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.*