# NM_018719.5(CDCA7L):c.878T>C (p.Phe293Ser)

https://sugi.bio/variant/cdca7l-p-phe293ser

## Summary

**CDCA7L p.Phe293Ser (c.878T>C)** is classified **Uncertain significance** in CDCA7L (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-26). AlphaMissense: ambiguous (0.3752); Very rare (popmax 0.00268%, afr).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense ambiguous · very rare (popmax 0.00268%, afr)

## For patients & families {#patients}

This is a change in the CDCA7L 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 | [CDCA7L](https://sugi.bio/atlas/gene/CDCA7L/) |
| Protein change (HGVS p.) | p.Phe293Ser |
| Coding change (HGVS c.) | c.878T>C |
| MANE Select transcript | [NM_018719](https://www.ncbi.nlm.nih.gov/nuccore/NM_018719) |
| Variant type | single nucleotide variant |
| Location | chr7:21906332-21906332 (GRCh38) |
| ClinVar | [VCV4223544](https://www.ncbi.nlm.nih.gov/clinvar/variation/4223544/) |

**All HGVS expressions:** `NC_000007.13:g.21945950A>G`, `NC_000007.14:g.21906332A>G`, `NM_001127370.3:c.776T>C`, `NM_001127371.3:c.740T>C`, `NM_018719.5:c.878T>C`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense makes no call; REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate — descriptive only.

- AlphaMissense **ambiguous** (0.3752) — no call either way
- REVEL 0.077 (moderately benign-leaning)
- SaProt LLR -2.254 (tolerated)
- → **In-silico consensus:** REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate
- Conservation: phyloP 9.192, GERP 0.955, phastCons 1 — highly conserved
- CADD: **PHRED 22.8**. 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 1.11** across the covering region of the MANE Select transcript (21,902,325–21,945,804), spanning 43,479 bp. Chi-square p 0.0085. 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 (A>C, Δ0.37 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 **0.00268%** (afr) · FAF95 0.000445% · FAF99 0.000167% · 2/74,546 in the highest group · 2/1,610,018 alleles overall — very rare (popmax 0.00268%, afr).

*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}

**CDCA7L** population constraint: LOEUF 0.983, pLI 2.6497e-12, missense-Z -0.6865. *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 66.23, 29% of residues very-high.

**2 experimental structure(s)** (PDB): [5YI9](https://www.rcsb.org/structure/5YI9), [6EMO](https://www.rcsb.org/structure/6EMO).

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-08-26.

**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 | 2025-08-26 |

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

## Similar variants {#similar}

Related CDCA7L variant pages (same residue, condition, or type): [DNAH11 p.Pro4458Leu](/variant/dnah11-p-pro4458leu), [DNAH11 p.Arg4437Cys](/variant/dnah11-p-arg4437cys), [DNAH11 p.Arg4437His](/variant/dnah11-p-arg4437his), [DNAH11 p.Arg4449Cys](/variant/dnah11-p-arg4449cys), [DNAH11 p.Gln4474Glu](/variant/dnah11-p-gln4474glu), [DNAH11 p.Gln4474Lys](/variant/dnah11-p-gln4474lys), [DNAH11 p.Glu4477Lys](/variant/dnah11-p-glu4477lys), [DNAH11 p.Glu4500Gly](/variant/dnah11-p-glu4500gly).

### 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 4223544). 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.*