# NM_031942.5(CDCA7):c.1057C>T (p.Arg353Cys)

https://sugi.bio/variant/cdca7-p-arg353cys

## Summary

**CDCA7 p.Arg353Cys (c.1057C>T)** is classified **Likely pathogenic** in CDCA7 (ClinVar, Single submitter, 2 submitters; last evaluated 2023-12-15). AlphaMissense: likely pathogenic (0.9947); Very rare (popmax 0.00223%, eas); Associated with immunodeficiency-centromeric instability-facial anomalies syndrome 3.

**At a glance:** Likely pathogenic · review: Single submitter · rsID rs879253738 · 2 submitters · 1 linked condition · AlphaMissense likely pathogenic · very rare (popmax 0.00223%, eas)

## For patients & families {#patients}

This is a change in the CDCA7 gene that is considered likely disease-causing, submitted by 2 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.Arg353Cys |
| Coding change (HGVS c.) | c.1057C>T |
| MANE Select transcript | [NM_031942](https://www.ncbi.nlm.nih.gov/nuccore/NM_031942) |
| dbSNP | [rs879253738](https://www.ncbi.nlm.nih.gov/snp/rs879253738/) |
| Variant type | single nucleotide variant |
| Location | chr2:173366304-173366304 (GRCh38) |
| ClinVar | [VCV225529](https://www.ncbi.nlm.nih.gov/clinvar/variation/225529/) |

**All HGVS expressions:** `NC_000002.11:g.174231032C>T`, `NC_000002.12:g.173366304C>T`, `NG_047202.1:g.17288C>T`, `NM_031942.5:c.1057C>T`, `NM_145810.3:c.820C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.9947) — concordant with the pathogenic call
- REVEL 0.619 (indeterminate)
- SaProt LLR -14.935 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this damaging; REVEL makes no call
- Conservation: phyloP 5.965, GERP 1.7, phastCons 1 — highly conserved (agrees)
- ⚠ **Isoform check:** AlphaMissense is numbered on a different transcript (AM **R274C** vs ClinVar **R353C**) — the AlphaMissense read here may be for a different residue; verify against the ClinVar transcript.
- AlphaMissense ranks this among the **top 8%** most-pathogenic-predicted substitutions in CDCA7 (of 2,165 modeled).
- CADD: **PHRED 32.0**. 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 0.18** across the covering region of the MANE Select transcript (173,365,587–173,366,314), spanning 727 bp — the region is depleted of missense variation. Chi-square p 0.00096. 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>A, Δ0.27 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 **0.00223%** (eas) · FAF95 0.000124% · FAF99 9e-05% · 1/44,862 in the highest group · 6/1,461,594 alleles overall — very rare (popmax 0.00223%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.00223% | 44,862 |
| European (non-Finnish) | 0.000424% | 235,975 |

*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}


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}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-12-15.

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

**Submission history:** 2 submissions (2019–2023); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| OMIM | Pathogenic | flagged submission | literature only | 2019-04-10 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely pathogenic | criteria provided, single submitter | clinical testing | 2023-12-15 |

## 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, none provided.

## Same-residue context {#hotspot}

Residue **353** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [CDCA7 p.Arg353His](/variant/cdca7-p-arg353his). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related CDCA7 variant pages (same residue, condition, or type): [CDCA7 p.Arg353His](/variant/cdca7-p-arg353his), [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).

### 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 225529). 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.*