# NM_138477.4(CDAN1):c.804C>A (p.Pro268=)

https://sugi.bio/variant/cdan1-p-pro268

## Summary

**CDAN1 p.Pro268= (c.804C>A)** is classified **Benign/Likely benign** in CDAN1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-06-01). Rare (popmax 0.275%, amr); Associated with anemia, congenital dyserythropoietic, type 1a.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs191624595 · 4 submitters · 1 linked condition · rare (popmax 0.275%, amr)

## For patients & families {#patients}

This is a change in the CDAN1 gene that is classified as benign/likely benign — not considered disease-causing, submitted by 4 submitters, and is linked to anemia, congenital dyserythropoietic, type 1a.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Age of onset (of this condition) | Adolescent, Adult, Childhood, Infancy, Neonatal |
| Prevalence | <1 / 1 000 000 (Europe) |
| Diagnostic panels | CDAN1 is a diagnostic-grade gene on 4 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0024649/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CDAN1](https://sugi.bio/atlas/gene/CDAN1/) |
| Protein change (HGVS p.) | p.Pro268= |
| Coding change (HGVS c.) | c.804C>A |
| MANE Select transcript | [NM_138477](https://www.ncbi.nlm.nih.gov/nuccore/NM_138477) |
| dbSNP | [rs191624595](https://www.ncbi.nlm.nih.gov/snp/rs191624595/) |
| Variant type | single nucleotide variant |
| Location | chr15:42735649-42735649 (GRCh38) |
| ClinVar | [VCV2054884](https://www.ncbi.nlm.nih.gov/clinvar/variation/2054884/) |

**All HGVS expressions:** `LRG_1164:g.6571C>A`, `LRG_1164t1:c.804C>A`, `NC_000015.10:g.42735649G>T`, `NC_000015.9:g.43027847G>T`, `NG_012491.1:g.6571C>A`, `NM_138477.4:c.804C>A`

## 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 -1.349, GERP -4.61 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 0.337**. 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 (G>C, Δ0.20 acceptor loss), 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 **0.275%** (amr) · FAF95 0.241% · FAF99 0.228% · 165/60,026 in the highest group · 276/1,614,076 alleles overall — rare (popmax 0.275%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.275% | 364 |
| Remaining individuals (not grpmax-eligible) | 0.0432% | 2,315 |
| African / African-American | 0.0133% | 7,502 |
| European (non-Finnish) | 0.00593% | 16,857 |
| East Asian | 0.00223% | 44,882 |
| South Asian | 0.0022% | 45,540 |
| Finnish (not grpmax-eligible) | 0.00156% | 63,964 |

*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}

**CDAN1** population constraint: LOEUF 0.908, pLI 1.6127e-27, missense-Z -1.1406; ClinGen dosage — haploinsufficiency gene assoc. with recessive phenotype, triplosensitivity 0/3. *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):

- **anemia, congenital dyserythropoietic, type 1a** — Definitive (AR)

## Protein context {#protein}

Residue **268** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 72.58, 32% of residues very-high.

**2 experimental structure(s)** (PDB): [9CVC](https://www.rcsb.org/structure/9CVC), [9IMZ](https://www.rcsb.org/structure/9IMZ).

## Clinical significance {#significance}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-06-01.

**Submitter consensus:** conflicting (3 Likely benign, 1 Benign).

**Submission history:** 4 submissions (2023–2026); 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 | 2023-10-17 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2025-12-29 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2026-06-01 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-06-06 |

## Associated conditions {#conditions}

[anemia, congenital dyserythropoietic, type 1a](https://sugi.bio/atlas/disease/anemia-congenital-dyserythropoietic-type-1a/).

**Reported phenotype names (ClinVar):** Anemia, congenital dyserythropoietic, type 1a, not provided, not specified, CDAN1-Related Congenital Dyserythropoietic Anemia, DYSERYTHROPOIETIC ANEMIA, CONGENITAL, TYPE Ia, AllHighlyPenetrant, none provided.

## Similar variants {#similar}

Related CDAN1 variant pages (same residue, condition, or type): [CDAN1 p.Pro268Arg](/variant/cdan1-p-pro268arg), [CDAN1 p.Pro268Ser](/variant/cdan1-p-pro268ser), [CDAN1 p.Arg1042Trp](/variant/cdan1-p-arg1042trp), [CDAN1 p.Arg682Ter](/variant/cdan1-p-arg682ter), [CDAN1 p.Arg714Trp](/variant/cdan1-p-arg714trp), [CDAN1 p.Asn599Ser](/variant/cdan1-p-asn599ser), [CDAN1 p.Phe52Leu](/variant/cdan1-p-phe52leu), [CDAN1 p.Pro1130Leu](/variant/cdan1-p-pro1130leu).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 2026-10-14); 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 2054884). 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.*