# NM_017895.8(DDX27):c.2113C>T (p.Pro705Ser)

https://sugi.bio/variant/ddx27-p-pro705ser

## Summary

**DDX27 p.Pro705Ser (c.2113C>T)** is classified **Uncertain significance** in DDX27 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-07). AlphaMissense: likely benign (0.0677); Very rare (popmax 0.000932%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs774804993 · 1 submitter · AlphaMissense likely benign · very rare (popmax 0.000932%, nfe)

## For patients & families {#patients}

This is a change in the DDX27 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 | [DDX27](https://sugi.bio/atlas/gene/DDX27/) |
| Protein change (HGVS p.) | p.Pro705Ser |
| Coding change (HGVS c.) | c.2113C>T |
| MANE Select transcript | [NM_017895](https://www.ncbi.nlm.nih.gov/nuccore/NM_017895) |
| dbSNP | [rs774804993](https://www.ncbi.nlm.nih.gov/snp/rs774804993/) |
| Variant type | single nucleotide variant |
| Location | chr20:49242203-49242203 (GRCh38) |
| ClinVar | [VCV2396776](https://www.ncbi.nlm.nih.gov/clinvar/variation/2396776/) |

**All HGVS expressions:** `NC_000020.10:g.47858740C>T`, `NC_000020.11:g.49242203C>T`, `NM_001348187.2:c.2206C>T`, `NM_017895.8:c.2113C>T`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.0677)
- REVEL 0.096 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -9.475 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 4.815, GERP 1.86, phastCons 1 — highly conserved (differs from AlphaMissense)
- ⚠ **Isoform check:** AlphaMissense is numbered on a different transcript (AM **P736S** vs ClinVar **P705S**) — the AlphaMissense read here may be for a different residue; verify against the ClinVar transcript.
- CADD: **PHRED 21.3**. 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 0.76** across the covering region of the MANE Select transcript (49,226,445–49,243,831), spanning 17,386 bp. Chi-square p 9e-11. 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, Δ0.92 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 **0.000932%** (nfe) · FAF95 0.0005% · FAF99 0.000366% · 11/1,179,980 in the highest group · 11/1,613,940 alleles overall — very rare (popmax 0.000932%, nfe).

*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}

**DDX27** population constraint: LOEUF 0.528, pLI 0.28736, missense-Z 2.4091. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **705** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 72.06, 24% of residues very-high.

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

*Describes the biological roles of DDX27 (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:** DDX27's established molecular role includes RNA binding. p.Pro705Ser falls in the disordered region.


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

**Molecular function:** RNA binding.

**Biological process:** rRNA processing.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-11-07.

**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 | 2022-11-07 |

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

## Similar variants {#similar}

Related DDX27 variant pages (same residue, condition, or type): [DDX27 p.Ala239=](/variant/ddx27-p-ala239), [DDX27 p.Glu172Lys](/variant/ddx27-p-glu172lys), [DDX27 c.52C>G](/variant/ddx27-c-52c-g), [DDX27 c.-33G>A](/variant/ddx27-c-minus-33g-a), [DDX27 p.Ala147Thr](/variant/ddx27-p-ala147thr), [DDX27 p.Ala256Thr](/variant/ddx27-p-ala256thr), [DDX27 p.Ala308Val](/variant/ddx27-p-ala308val), [DDX27 p.Ala553Val](/variant/ddx27-p-ala553val).

### 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 2026-07-14); 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 2396776). 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.*