# NM_003719.5(PDE8B):c.1533C>T (p.Asp511=)

https://sugi.bio/variant/pde8b-p-asp511

## Summary

**PDE8B p.Asp511= (c.1533C>T)** is classified **Likely benign** in PDE8B (ClinVar, Single submitter, 2 submitters; last evaluated 2024-01-09). Ultra-rare (popmax 0.0683%, amr).

**At a glance:** Likely benign · review: Single submitter · rsID rs148282450 · 2 submitters · ultra-rare (popmax 0.0683%, amr)

## For patients & families {#patients}

This is a change in the PDE8B gene that is classified as likely benign — not considered disease-causing, submitted by 2 submitters.

*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 | [PDE8B](https://sugi.bio/atlas/gene/PDE8B/) |
| Protein change (HGVS p.) | p.Asp511= |
| Coding change (HGVS c.) | c.1533C>T |
| MANE Select transcript | [NM_003719](https://www.ncbi.nlm.nih.gov/nuccore/NM_003719) |
| dbSNP | [rs148282450](https://www.ncbi.nlm.nih.gov/snp/rs148282450/) |
| Variant type | single nucleotide variant |
| Location | chr5:77411678-77411678 (GRCh38) |
| ClinVar | [VCV708098](https://www.ncbi.nlm.nih.gov/clinvar/variation/708098/) |

**All HGVS expressions:** `NC_000005.10:g.77411678C>T`, `NC_000005.9:g.76707503C>T`, `NG_023364.2:g.236427C>T`, `NM_001029851.4:c.1242C>T`, `NM_001029852.4:c.1368C>T`, `NM_001029853.4:c.1473C>T`, `NM_001029854.4:c.1392C>T`, `NM_001349748.3:c.1530C>T`, `NM_001349749.3:c.1596C>T`, `NM_001349750.3:c.1293C>T`, `NM_001349751.3:c.1530C>T`, `NM_001349752.3:c.1227C>T`, `NM_001349753.2:c.1161C>T`, `NM_001376062.1:c.1230C>T`, `NM_001376063.1:c.1524C>T`, `NM_001376064.1:c.1383C>T`, `NM_001376065.1:c.1239C>T`, `NM_001376066.1:c.1170C>T`, `NM_001376067.1:c.1161C>T`, `NM_001376068.1:c.1161C>T`, `NM_001376069.1:c.1149C>T`, `NM_001376070.1:c.1089C>T`, `NM_001376071.1:c.1086C>T`, `NM_001376072.1:c.1230C>T`, `NM_001376073.1:c.939C>T`, `NM_001376074.1:c.879C>T`, `NM_001376075.1:c.870C>T`, `NM_003719.5:c.1533C>T`

## 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 0.055, GERP -2.18, phastCons 0.972 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 9.797**. 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 (C>A, Δ0.68 acceptor 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 **0.0683%** (amr) · FAF95 0.0517% · FAF99 0.0459% · 41/59,996 in the highest group · 553/1,609,446 alleles overall — ultra-rare (popmax 0.0683%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.0683% | 1,463 |
| European (non-Finnish) | 0.0411% | 2,435 |
| Remaining individuals (not grpmax-eligible) | 0.024% | 4,159 |
| East Asian | 0.0112% | 8,968 |
| African / African-American | 0.00668% | 14,980 |
| South Asian | 0.0044% | 22,747 |

*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}

**PDE8B** population constraint: LOEUF 0.351, pLI 1, missense-Z 3.3877. *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 74.88, 50% of residues very-high.

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

*Describes the biological roles of PDE8B (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:** PDE8B's established molecular role includes 3',5'-cyclic-AMP phosphodiesterase activity.


### Pathways affected {#pathways}

PDE8B participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [G alpha (s) signalling events](https://reactome.org/content/detail/R-HSA-418555) | curated |

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

**Molecular function:** 3',5'-cyclic-AMP phosphodiesterase activity.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-01-09.

**Submitter consensus:** unanimous (2/2 Likely benign).

**Submission history:** 2 submissions (2023–2024); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2023-07-28 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2024-01-09 |

**Reported phenotype names (ClinVar):** not provided, PDE8B-related disorder, PDE8B-related condition, none provided.

## Similar variants {#similar}

Related PDE8B variant pages (same residue, condition, or type): [PDE8B c.*498C>A](/variant/pde8b-c-star-498c-a), [PDE8B p.Ala232Ser](/variant/pde8b-p-ala232ser), [PDE8B p.Ala4Val](/variant/pde8b-p-ala4val), [PDE8B p.Ala65Pro](/variant/pde8b-p-ala65pro), [PDE8B p.Ala70Ser](/variant/pde8b-p-ala70ser), [PDE8B p.Ala86Thr](/variant/pde8b-p-ala86thr), [PDE8B p.Arg237Lys](/variant/pde8b-p-arg237lys), [PDE8B p.Arg483Trp](/variant/pde8b-p-arg483trp).

### 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 708098). 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.*