# NM_007217.4(PDCD10):c.211dup (p.Ser71fs)

https://sugi.bio/variant/pdcd10-p-ser71fs

## Summary

**PDCD10 p.Ser71fs (c.211dup)** is classified **Pathogenic** in PDCD10 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-11-24). No allele count reported in gnomAD v4.1 (AN 1,611,932); Associated with cerebral cavernous malformation 3.

**At a glance:** Pathogenic · review: Multiple submitters · rsID rs2108409355 · 2 submitters · 1 linked condition · no allele count reported in gnomAD v4.1 (AN 1,611,932)

## For patients & families {#patients}

This is a change in the PDCD10 gene that is considered disease-causing, submitted by 2 submitters, and is linked to cerebral cavernous malformation 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.*

|  |  |
| --- | --- |
| Clinical trials | 1 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0018314/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [PDCD10](https://sugi.bio/atlas/gene/PDCD10/) |
| Protein change (HGVS p.) | p.Ser71fs |
| Coding change (HGVS c.) | c.211dup |
| MANE Select transcript | [NM_007217](https://www.ncbi.nlm.nih.gov/nuccore/NM_007217) |
| dbSNP | [rs2108409355](https://www.ncbi.nlm.nih.gov/snp/rs2108409355/) |
| Variant type | Duplication |
| Location | chr3:167697065-167697066 (GRCh38) |
| ClinVar | [VCV1076520](https://www.ncbi.nlm.nih.gov/clinvar/variation/1076520/) |

**All HGVS expressions:** `LRG_651:g.42798dup`, `LRG_651t1:c.211dup`, `NC_000003.11:g.167414860dup`, `NC_000003.12:g.167697072dup`, `NG_008158.1:g.42798dup`, `NM_007217.4:c.211dup`, `NM_145859.2:c.211dup`, `NM_145860.2:c.211dup`

## Computational & population evidence {#evidence}

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

- **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 4.072, GERP 2.52, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.924, pLI 0.6364. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 5 of 9**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no duplication variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no allele count reported in gnomAD v4.1 (AN 1,611,932)** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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}

**PDCD10** population constraint: LOEUF 0.924, pLI 0.6364, missense-Z 0.6011. *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 90.82, 83% of residues very-high.

**10 experimental structure(s)** (PDB): [3AJM](https://www.rcsb.org/structure/3AJM), [3L8I](https://www.rcsb.org/structure/3L8I), [3L8J](https://www.rcsb.org/structure/3L8J), [3RQE](https://www.rcsb.org/structure/3RQE), [3RQF](https://www.rcsb.org/structure/3RQF), [3RQG](https://www.rcsb.org/structure/3RQG).

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

*Describes the biological roles of PDCD10 (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:** PDCD10's established molecular role includes protein homodimerization activity.


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

**Molecular function:** protein homodimerization activity.

**Biological process:** positive regulation of cell population proliferation, positive regulation of gene expression, negative regulation of gene expression, positive regulation of cell migration, positive regulation of stress-activated MAPK cascade, positive regulation of peptidyl-serine phosphorylation.

## Clinical significance {#significance}

**Pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2022-11-24.

**Submitter consensus:** unanimous (2/2 Pathogenic).

**Submission history:** 2 submissions (2020–2022); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2020-01-23 |
| Blueprint Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2022-11-24 |

## Associated conditions {#conditions}

[cerebral cavernous malformation 3](https://sugi.bio/atlas/disease/cerebral-cavernous-malformation-3/).

**Reported phenotype names (ClinVar):** Cerebral cavernous malformation 3, PDCD10-related disorder, Familial Cerebral Cavernous Malformation 3, PDCD10-related condition.

## Similar variants {#similar}

Related PDCD10 variant pages (same residue, condition, or type): [PDCD10 p.Ser71Asn](/variant/pdcd10-p-ser71asn), [PDCD10 p.Ser71=](/variant/pdcd10-p-ser71), [PDCD10 p.Asn195fs](/variant/pdcd10-p-asn195fs), [PDCD10 p.Thr177fs](/variant/pdcd10-p-thr177fs), [PDCD10 p.Ile198fs](/variant/pdcd10-p-ile198fs), [PDCD10 p.Met26fs](/variant/pdcd10-p-met26fs), [PDCD10 p.Thr144fs](/variant/pdcd10-p-thr144fs), [PDCD10 p.Thr77fs](/variant/pdcd10-p-thr77fs).

### 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 1076520). 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.*