# NM_003000.3(SDHB):c.201A>G (p.Lys67=)

https://sugi.bio/variant/sdhb-p-lys67

## Summary

**SDHB p.Lys67= (c.201A>G)** is classified **Conflicting classifications of pathogenicity** in SDHB (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-09-04). Very rare (popmax 0.000255%, nfe); Associated with pheochromocytoma.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs1436421650 · 2 submitters · 4 linked conditions · very rare (popmax 0.000255%, nfe)

## For patients & families {#patients}

This is a change in the SDHB gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 2 submitters, and is linked to pheochromocytoma.

*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 | 121 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0015105/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.Lys67= |
| Coding change (HGVS c.) | c.201A>G |
| MANE Select transcript | [NM_003000](https://www.ncbi.nlm.nih.gov/nuccore/NM_003000) |
| dbSNP | [rs1436421650](https://www.ncbi.nlm.nih.gov/snp/rs1436421650/) |
| Variant type | single nucleotide variant |
| Location | chr1:17033145-17033145 (GRCh38) |
| ClinVar | [VCV1019887](https://www.ncbi.nlm.nih.gov/clinvar/variation/1019887/) |

**All HGVS expressions:** `LRG_316:g.26026A>G`, `LRG_316t1:c.201A>G`, `NC_000001.10:g.17359640T>C`, `NC_000001.11:g.17033145T>C`, `NG_012340.1:g.26026A>G`, `NM_003000.3:c.201A>G`

## 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 -0.777, GERP -4.39, phastCons 0.008 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 6.642**. 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 (T>A, Δ0.30 acceptor loss), 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 **0.000255%** (nfe) · FAF95 6.8e-05% · FAF99 1.9e-05% · 3/1,175,166 in the highest group · 3/1,456,554 alleles overall — very rare (popmax 0.000255%, 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}

**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 **67** lies in the 2fe-2s ferredoxin-type domain; a β-strand.

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. p.Lys67= falls in the 2fe-2s ferredoxin-type domain.


### 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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2024-09-04.

**Submitter consensus:** conflicting (1 Likely benign, 1 Uncertain significance).

**Submission history:** 2 submissions (2019–2024); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2019-04-19 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-09-04 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Pheochromocytoma, Gastrointestinal stromal tumor, Pheochromocytoma/paraganglioma syndrome 4, Hereditary cancer-predisposing syndrome, MAX-Related Hereditary Paraganglioma-Pheochromocytoma Syndrome, Gastrointestinal stromal tumor, somatic, Gastrointestinal stroma tumor, CAROTID BODY TUMORS AND MULTIPLE EXTRAADRENAL PHEOCHROMOCYTOMAS, SDHB-Related Hereditary Paraganglioma-Pheochromocytoma Syndrome (Paragangliomas 4), Paragangliomas 4.

## Similar variants {#similar}

Related SDHB variant pages (same residue, condition, or type): [SDHB p.Lys67Thr](/variant/sdhb-p-lys67thr), [SDHB c.200+1G>A](/variant/sdhb-c-200-plus-1g-a), [SDHB c.200+1G>C](/variant/sdhb-c-200-plus-1g-c), [SDHB c.200+5G>T](/variant/sdhb-c-200-plus-5g-t), [SDHB c.201-1G>C](/variant/sdhb-c-201-minus-1g-c), [SDHB c.201-2A>C](/variant/sdhb-c-201-minus-2a-c), [SDHB c.286+1G>A](/variant/sdhb-c-286-plus-1g-a), [SDHB c.286+2T>A](/variant/sdhb-c-286-plus-2t-a).

### 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 1019887). 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.*