# NM_003002.4(SDHD):c.171T>C (p.Ser57=)

https://sugi.bio/variant/sdhd-p-ser57

## Summary

**SDHD p.Ser57= (c.171T>C)** is classified **Benign/Likely benign** in SDHD (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-03-17). Absent from gnomAD v4.1; Associated with pheochromocytoma/paraganglioma syndrome 1.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs2135269133 · 2 submitters · 4 linked conditions · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the SDHD gene that is classified as benign/likely benign — not considered disease-causing, submitted by 2 submitters, and is linked to pheochromocytoma/paraganglioma syndrome 1.

*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/0007324/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [SDHD](https://sugi.bio/atlas/gene/SDHD/) |
| Protein change (HGVS p.) | p.Ser57= |
| Coding change (HGVS c.) | c.171T>C |
| MANE Select transcript | [NM_003002](https://www.ncbi.nlm.nih.gov/nuccore/NM_003002) |
| dbSNP | [rs2135269133](https://www.ncbi.nlm.nih.gov/snp/rs2135269133/) |
| Variant type | single nucleotide variant |
| Location | chr11:112088868-112088868 (GRCh38) |
| ClinVar | [VCV1153031](https://www.ncbi.nlm.nih.gov/clinvar/variation/1153031/) |

**All HGVS expressions:** `LRG_9:g.7022T>C`, `LRG_9t1:c.171T>C`, `NC_000011.10:g.112088868T>C`, `NC_000011.9:g.111959592T>C`, `NG_012337.3:g.7022T>C`, `NG_033145.1:g.2931A>G`, `NM_001276503.2:c.169+895T>C`, `NM_001276504.2:c.54T>C`, `NM_001276506.2:c.171T>C`, `NM_003002.4:c.171T>C`, `NR_077060.2:n.206T>C`

## 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 1.482, GERP 2.14, phastCons 1 — weakly conserved position
- CADD: **PHRED 15.01**. 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, Δ0.45 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: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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}

**SDHD** population constraint: LOEUF 0.581, pLI 0.90513, missense-Z 0.80794; ClinGen dosage — haploinsufficiency 3/3, triplosensitivity 0/3. *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** — Limited (AR)
- **hereditary pheochromocytoma-paraganglioma** — Definitive (AD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 81.50, 63% of residues very-high.

**2 experimental structure(s)** (PDB): [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 SDHD (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.*


### Pathways affected {#pathways}

SDHD 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}

**Biological process:** tricarboxylic acid cycle.

## Clinical significance {#significance}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-03-17.

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

**Submission history:** 2 submissions (2019–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2019-12-16 |
| Myriad Genetics, Inc. | Benign | criteria provided, single submitter | clinical testing | 2025-03-17 |

## Associated conditions {#conditions}

[pheochromocytoma/paraganglioma syndrome 1](https://sugi.bio/atlas/disease/pheochromocytoma-paraganglioma-syndrome-1/), [pheochromocytoma](https://sugi.bio/atlas/disease/pheochromocytoma/), [Carney-Stratakis syndrome](https://sugi.bio/atlas/disease/carney-stratakis-syndrome/), [Cowden syndrome 3](https://sugi.bio/atlas/disease/cowden-syndrome-3/).

**Reported phenotype names (ClinVar):** Pheochromocytoma/paraganglioma syndrome 1, Carney-Stratakis syndrome, Cowden syndrome 3, Paragangliomas with sensorineural hearing loss, Pheochromocytoma, Paragangliomas 1, Glomus tumors familial 1, Paraganglioma - glomus jugulare, SDHD-Related Hereditary Paraganglioma-Pheochromocytoma Syndrome, PARAGANGLIOMAS, FAMILIAL NONCHROMAFFIN, 1.

## Similar variants {#similar}

Related SDHD variant pages (same residue, condition, or type): [SDHD p.Ser57Cys](/variant/sdhd-p-ser57cys), [SDHD p.Ser57Phe](/variant/sdhd-p-ser57phe), [SDHD c.170-1G>T](/variant/sdhd-c-170-minus-1g-t), [SDHD c.170-2A>G](/variant/sdhd-c-170-minus-2a-g), [SDHD c.314+1G>A](/variant/sdhd-c-314-plus-1g-a), [SDHD c.314+1G>T](/variant/sdhd-c-314-plus-1g-t), [SDHD c.315-1G>A](/variant/sdhd-c-315-minus-1g-a), [SDHD c.315-2A>C](/variant/sdhd-c-315-minus-2a-c).

### 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 1153031). 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.*