# NM_003000.3(SDHB):c.385C>T (p.Pro129Ser)

https://sugi.bio/variant/sdhb-p-pro129ser

## Summary

**SDHB p.Pro129Ser (c.385C>T)** is classified **Uncertain significance** in SDHB (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-01-02). AlphaMissense: likely pathogenic (0.9783); Very rare (popmax 8.47e-05%, nfe); Associated with hereditary neoplastic syndrome.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs1553177740 · 3 submitters · 6 linked conditions · AlphaMissense likely pathogenic · very rare (popmax 8.47e-05%, nfe)

## For patients & families {#patients}

This is a change in the SDHB gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 3 submitters, and is linked to hereditary neoplastic syndrome.

*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 | 31 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0019921/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.Pro129Ser |
| Coding change (HGVS c.) | c.385C>T |
| MANE Select transcript | [NM_003000](https://www.ncbi.nlm.nih.gov/nuccore/NM_003000) |
| dbSNP | [rs1553177740](https://www.ncbi.nlm.nih.gov/snp/rs1553177740/) |
| Variant type | single nucleotide variant |
| Location | chr1:17028638-17028638 (GRCh38) |
| ClinVar | [VCV824312](https://www.ncbi.nlm.nih.gov/clinvar/variation/824312/) |

**All HGVS expressions:** `LRG_316:g.30533C>T`, `LRG_316t1:c.385C>T`, `NC_000001.10:g.17355133G>A`, `NC_000001.11:g.17028638G>A`, `NG_012340.1:g.30533C>T`, `NM_003000.3:c.385C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.9783)
- REVEL 0.949 (strongly pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -14.462 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 11.893, GERP 2.2, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 32.0**. 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 0.98** across the covering region of the MANE Select transcript (17,018,884–17,054,019), spanning 35,135 bp. Chi-square p 0.67. 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 (G>C, Δ0.23 donor 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 **8.47e-05%** (nfe) · 1/1,179,986 in the highest group · 1/1,461,844 alleles overall — very rare (popmax 8.47e-05%, 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 **129** lies in the 2fe-2s ferredoxin-type domain.

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.Pro129Ser 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}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-01-02.

**Submitter consensus:** unanimous (3/3 Uncertain significance).

**Submission history:** 3 submissions (2024–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-01-28 |
| Fulgent Genetics, Fulgent Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-02-24 |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-01-02 |

## Associated conditions {#conditions}

[hereditary neoplastic syndrome](https://sugi.bio/atlas/disease/hereditary-neoplastic-syndrome/), [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/), [Carney-Stratakis syndrome](https://sugi.bio/atlas/disease/carney-stratakis-syndrome/), [mitochondrial complex 2 deficiency, nuclear type 4](https://sugi.bio/atlas/disease/mitochondrial-complex-2-deficiency-nuclear-type-4/).

**Reported phenotype names (ClinVar):** Hereditary cancer-predisposing syndrome, Gastrointestinal stromal tumor, Pheochromocytoma, Pheochromocytoma/paraganglioma syndrome 4, Carney-Stratakis syndrome, Mitochondrial complex 2 deficiency, nuclear type 4, Neoplastic Syndromes, Hereditary, Tumor predisposition, Hereditary Cancer Syndrome, Hereditary neoplastic syndrome.

## Same-residue context {#hotspot}

Residue **129** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [SDHB p.Pro129Arg](/variant/sdhb-p-pro129arg). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related SDHB variant pages (same residue, condition, or type): [SDHB p.Pro129Ala](/variant/sdhb-p-pro129ala), [SDHB p.Pro129Arg](/variant/sdhb-p-pro129arg), [SDHB p.Pro129Thr](/variant/sdhb-p-pro129thr), [SDHB p.Pro129=](/variant/sdhb-p-pro129), [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).

### 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 824312). 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.*