# NM_003000.3(SDHB):c.716_719del (p.Ser239fs)

https://sugi.bio/variant/sdhb-p-ser239fs

## Summary

**SDHB p.Ser239fs (c.716_719del)** is classified **Pathogenic** in SDHB (ClinVar, Multiple submitters, 5 submitters; last evaluated 2024-10-20). No gnomAD frequency available for this variant; Associated with pheochromocytoma/paraganglioma syndrome 4.

**At a glance:** Pathogenic · review: Multiple submitters · rsID rs587781266 · 5 submitters · 5 linked conditions · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the SDHB gene that is considered disease-causing, submitted by 5 submitters, and is linked to pheochromocytoma/paraganglioma syndrome 4.

*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:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0010546/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [SDHB](https://sugi.bio/atlas/gene/SDHB/) |
| Protein change (HGVS p.) | p.Ser239fs |
| Coding change (HGVS c.) | c.716_719del |
| MANE Select transcript | [NM_003000](https://www.ncbi.nlm.nih.gov/nuccore/NM_003000) |
| dbSNP | [rs587781266](https://www.ncbi.nlm.nih.gov/snp/rs587781266/) |
| Variant type | Microsatellite |
| Location | chr1:17022654-17022657 (GRCh38) |
| ClinVar | [VCV12782](https://www.ncbi.nlm.nih.gov/clinvar/variation/12782/) |

**All HGVS expressions:** `LRG_316:g.36512CT[1]`, `LRG_316t1:c.716_719del`, `NC_000001.10:g.17349150GA[1]`, `NC_000001.11:g.17022655GA[1]`, `NG_012340.1:g.36512CT[1]`, `NM_003000.2:c.716_719delCTCT`, `NM_003000.3:c.716_719del`

## 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 -0.909, GERP -4.39, phastCons 0.001 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. ClinGen curates **sufficient evidence for haploinsufficiency** in this gene, supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **within the last 50 nt of the penultimate exon (7 of 8, 46 nt from its 3' end)** — predicted to **escape NMD**, so the truncated protein is likely expressed. An input to PVS1, not an applied code.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no microsatellite variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — 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}

**SDHB** population constraint: LOEUF 0.741, pLI 0.027807, missense-Z 0.43592; ClinGen dosage — haploinsufficiency 3, triplosensitivity 0 (0–3 scale). *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):

- **mitochondrial disease** — Definitive (AR)
- **hereditary pheochromocytoma-paraganglioma** — Definitive (AD)

## Protein context {#protein}

Residue **239** lies in a turn.

AlphaFold model confidence (whole protein): pLDDT 92.14, 86% of residues very-high.

**6 experimental structure(s)** (PDB): [7KCL](https://www.rcsb.org/structure/7KCL), [7KCM](https://www.rcsb.org/structure/7KCM), [7KLU](https://www.rcsb.org/structure/7KLU), [7KLV](https://www.rcsb.org/structure/7KLV), [8GS8](https://www.rcsb.org/structure/8GS8), [9KC4](https://www.rcsb.org/structure/9KC4).

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

*Describes the biological roles of SDHB (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:** SDHB's established molecular role includes succinate dehydrogenase (quinone) activity.


### Pathways affected {#pathways}

SDHB participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Citric acid cycle (TCA cycle)](https://reactome.org/content/detail/R-HSA-71403) | curated |
| [Maturation of TCA enzymes and regulation of TCA cycle](https://reactome.org/content/detail/R-HSA-9854311) | curated |
| [Respiratory electron transport](https://reactome.org/content/detail/R-HSA-611105) | electronic |

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

**Molecular function:** succinate dehydrogenase (quinone) activity.

## Clinical significance {#significance}

**Pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-10-20.

**Submitter consensus:** unanimous (5/5 Pathogenic).

**Submission history:** 5 submissions (2002–2024); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2002-05-09 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2024-10-20 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Pathogenic | criteria provided, single submitter | clinical testing | 2021-11-26 |
| Myriad Genetics, Inc. | Pathogenic | criteria provided, single submitter | clinical testing | 2024-02-08 |
| Ambry Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2023-03-28 |

## Associated conditions {#conditions}

[pheochromocytoma/paraganglioma syndrome 4](https://sugi.bio/atlas/disease/pheochromocytoma-paraganglioma-syndrome-4/), [pheochromocytoma](https://sugi.bio/atlas/disease/pheochromocytoma/), [gastrointestinal stromal tumor](https://sugi.bio/atlas/disease/gastrointestinal-stromal-tumor/), [hereditary neoplastic syndrome](https://sugi.bio/atlas/disease/hereditary-neoplastic-syndrome/), [hereditary pheochromocytoma-paraganglioma](https://sugi.bio/atlas/disease/hereditary-pheochromocytoma-paraganglioma/).

**Reported phenotype names (ClinVar):** Pheochromocytoma/paraganglioma syndrome 4, Hereditary cancer-predisposing syndrome, Gastrointestinal stromal tumor, Pheochromocytoma, Hereditary pheochromocytoma and paraganglioma, Paragangliomas 4, CAROTID BODY TUMORS AND MULTIPLE EXTRAADRENAL PHEOCHROMOCYTOMAS, SDHB-Related Hereditary Paraganglioma-Pheochromocytoma Syndrome (Paragangliomas 4), PARAGANGLIOMA, FAMILIAL MALIGNANT, PARAGANGLIOMAS, HEREDITARY EXTRAADRENAL.

## Similar variants {#similar}

Related SDHB variant pages (same residue, condition, or type): [SDHB p.Ser239Cys](/variant/sdhb-p-ser239cys), [SDHB p.Ser239Phe](/variant/sdhb-p-ser239phe), [SDHB p.Ser239Tyr](/variant/sdhb-p-ser239tyr), [SDHB p.Ser239=](/variant/sdhb-p-ser239), [SDHB p.Ser239Pro](/variant/sdhb-p-ser239pro), [SDHB p.Ala190fs](/variant/sdhb-p-ala190fs), [SDHB p.Leu111fs](/variant/sdhb-p-leu111fs), [SDHB p.Thr227fs](/variant/sdhb-p-thr227fs).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); 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 12782). 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.*