# NM_031942.5(CDCA7):c.312C>T (p.Ala104=)

https://sugi.bio/variant/cdca7-p-ala104

## Summary

**CDCA7 p.Ala104= (c.312C>T)** is classified **Benign/Likely benign** in CDCA7 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-19). Rare (popmax 0.712%, sas).

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs544881819 · 3 submitters · rare (popmax 0.712%, sas)

## For patients & families {#patients}

This is a change in the CDCA7 gene that is classified as benign/likely benign — not considered disease-causing, submitted by 3 submitters.

*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 | [CDCA7](https://sugi.bio/atlas/gene/CDCA7/) |
| Protein change (HGVS p.) | p.Ala104= |
| Coding change (HGVS c.) | c.312C>T |
| MANE Select transcript | [NM_031942](https://www.ncbi.nlm.nih.gov/nuccore/NM_031942) |
| dbSNP | [rs544881819](https://www.ncbi.nlm.nih.gov/snp/rs544881819/) |
| Variant type | single nucleotide variant |
| Location | chr2:173359419-173359419 (GRCh38) |
| ClinVar | [VCV1649286](https://www.ncbi.nlm.nih.gov/clinvar/variation/1649286/) |

**All HGVS expressions:** `NC_000002.11:g.174224147C>T`, `NC_000002.12:g.173359419C>T`, `NG_047202.1:g.10403C>T`, `NM_031942.5:c.312C>T`, `NM_145810.3:c.147+582C>T`

## 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 (below), not from a missing predictor score.
- Conservation: phyloP 2.248, GERP 0.055, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 15.37**. 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: **below the reporting threshold**. This position is scored for a different substitution (C>A, Δ0.22 donor 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 **0.712%** (sas) · FAF95 0.667% · FAF99 0.649% · 649/91,088 in the highest group · 719/1,614,012 alleles overall — rare (popmax 0.712%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.712% | 140 |
| Remaining individuals (not grpmax-eligible) | 0.0592% | 1,689 |
| Admixed American | 0.01% | 10,001 |
| East Asian | 0.00669% | 14,957 |
| African / African-American | 0.00267% | 37,491 |
| European (non-Finnish) | 0.00186% | 53,637 |

*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 **104** lies in the 'disordered' region.

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. p.Ala104= falls in the disordered region.


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

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

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

## Clinical significance {#significance}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-01-19.

**Submitter consensus:** conflicting (2 Benign, 1 Likely benign).

**Submission history:** 3 submissions (2024–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-01-19 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-19 |

**Reported phenotype names (ClinVar):** not provided, not specified, AllHighlyPenetrant, none provided.

## Similar variants {#similar}

Related CDCA7 variant pages (same residue, condition, or type): [CDCA7 c.384+2T>C](/variant/cdca7-c-384-plus-2t-c), [CDCA7 p.Ala157Val](/variant/cdca7-p-ala157val), [CDCA7 p.Ala391Gly](/variant/cdca7-p-ala391gly), [CDCA7 p.Arg134Leu](/variant/cdca7-p-arg134leu), [CDCA7 p.Arg134Trp](/variant/cdca7-p-arg134trp), [CDCA7 p.Arg171Cys](/variant/cdca7-p-arg171cys), [CDCA7 p.Arg171Leu](/variant/cdca7-p-arg171leu), [CDCA7 p.Arg239Gln](/variant/cdca7-p-arg239gln).

### 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 1649286). 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.*