# NM_032346.2(PDCD2L):c.47C>G (p.Pro16Arg)

https://sugi.bio/variant/pdcd2l-p-pro16arg

## Summary

**PDCD2L p.Pro16Arg (c.47C>G)** is classified **Uncertain significance** in PDCD2L (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-26). AlphaMissense: likely benign (0.0853); Ultra-rare (popmax 0.0219%, mid).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs61741229 · 1 submitter · AlphaMissense likely benign · ultra-rare (popmax 0.0219%, mid)

## For patients & families {#patients}

This is a change in the PDCD2L 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 | [PDCD2L](https://sugi.bio/atlas/gene/PDCD2L/) |
| Protein change (HGVS p.) | p.Pro16Arg |
| Coding change (HGVS c.) | c.47C>G |
| MANE Select transcript | [NM_032346](https://www.ncbi.nlm.nih.gov/nuccore/NM_032346) |
| dbSNP | [rs61741229](https://www.ncbi.nlm.nih.gov/snp/rs61741229/) |
| Variant type | single nucleotide variant |
| Location | chr19:34404477-34404477 (GRCh38) |
| ClinVar | [VCV3210573](https://www.ncbi.nlm.nih.gov/clinvar/variation/3210573/) |

**All HGVS expressions:** `NC_000019.10:g.34404477C>G`, `NC_000019.9:g.34895382C>G`, `NM_001353433.2:c.47C>G`, `NM_032346.2:c.47C>G`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.0853)
- REVEL 0.03 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -8.949 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 1.608, GERP 1.54, phastCons 0.616 — weakly conserved position
- CADD: **PHRED 20.6**. 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 1.04** across the covering region of the MANE Select transcript (34,404,431–34,426,117), spanning 21,686 bp. Chi-square p 0.44. 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, Δ0.41 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 **0.0219%** (mid) · FAF95 0.00126% · FAF99 0.00107% · 1/4,568 in the highest group · 24/1,544,034 alleles overall — ultra-rare (popmax 0.0219%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.0219% | 4,568 |
| European (non-Finnish) | 0.00192% | 52,113 |
| Remaining individuals (not grpmax-eligible) | 0.00167% | 59,852 |

*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}

**PDCD2L** population constraint: LOEUF 1.374, pLI 9.5048e-12, missense-Z -0.32319. *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 75.93, 40% of residues very-high.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-12-26.

**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 | 2023-12-26 |

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

## Similar variants {#similar}

Related PDCD2L variant pages (same residue, condition, or type): [PDCD2L p.Ala111Val](/variant/pdcd2l-p-ala111val), [PDCD2L p.Ala174Thr](/variant/pdcd2l-p-ala174thr), [PDCD2L p.Ala175Val](/variant/pdcd2l-p-ala175val), [PDCD2L p.Ala258Val](/variant/pdcd2l-p-ala258val), [PDCD2L p.Ala2Val](/variant/pdcd2l-p-ala2val), [PDCD2L p.Ala38Ser](/variant/pdcd2l-p-ala38ser), [PDCD2L p.Ala44Ser](/variant/pdcd2l-p-ala44ser), [PDCD2L p.Ala81Thr](/variant/pdcd2l-p-ala81thr).

### 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 3210573). 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.*