# NM_003002.4(SDHD):c.70C>T (p.Pro24Ser)

https://sugi.bio/variant/sdhd-p-pro24ser

## Summary

**SDHD p.Pro24Ser (c.70C>T)** is classified **Conflicting classifications of pathogenicity** in SDHD (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-06-17). AlphaMissense: likely benign (0.0689); Absent from gnomAD v4.1; Associated with Carney-Stratakis syndrome.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs775986509 · 3 submitters · 5 linked conditions · AlphaMissense likely benign · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the SDHD gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 3 submitters, and is linked to Carney-Stratakis 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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant |
| Age of onset (of this condition) | Adolescent, Adult |
| Clinical trials | 1 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | SDHD is a diagnostic-grade gene on 15 Genomics England panels |

**Commonly reported features of Carney-Stratakis syndrome** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Paraganglioma — Very frequent (99-80%)
- Gastrointestinal stroma tumor — Very frequent (99-80%)
- Tinnitus — Frequent (79-30%)
- Hearing impairment — Frequent (79-30%)
- Weight loss — Frequent (79-30%)
- Dysphagia — Frequent (79-30%)
- Abdominal pain — Frequent (79-30%)
- Gastrointestinal hemorrhage — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0010643/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.Pro24Ser |
| Coding change (HGVS c.) | c.70C>T |
| MANE Select transcript | [NM_003002](https://www.ncbi.nlm.nih.gov/nuccore/NM_003002) |
| dbSNP | [rs775986509](https://www.ncbi.nlm.nih.gov/snp/rs775986509/) |
| Variant type | single nucleotide variant |
| Location | chr11:112087874-112087874 (GRCh38) |
| ClinVar | [VCV1473419](https://www.ncbi.nlm.nih.gov/clinvar/variation/1473419/) |

**All HGVS expressions:** `LRG_9:g.6028C>T`, `LRG_9t1:c.70C>T`, `NC_000011.10:g.112087874C>T`, `NC_000011.9:g.111958598C>T`, `NG_012337.3:g.6028C>T`, `NG_033145.1:g.3925G>A`, `NM_001276503.2:c.70C>T`, `NM_001276504.2:c.52+915C>T`, `NM_001276506.2:c.70C>T`, `NM_003002.4:c.70C>T`, `NR_077060.2:n.105C>T`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely benign** (0.0689)
- REVEL 0.59 (indeterminate)
- SaProt LLR -6.882 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate
- Conservation: phyloP 0.168, GERP -3.88 — weakly conserved position
- CADD: **PHRED 3.894**. 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 0.83** across the covering region of the MANE Select transcript (112,086,908–112,094,967), spanning 8,059 bp. Chi-square p 0.019. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- 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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2025-06-17.

**Submitter consensus:** conflicting (2 Uncertain significance, 1 Likely benign).

**Submission history:** 3 submissions (2021–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-08-30 |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2022-06-22 |
| Color Diagnostics, LLC DBA Color Health | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-06-17 |

## Associated conditions {#conditions}

[Carney-Stratakis syndrome](https://sugi.bio/atlas/disease/carney-stratakis-syndrome/), [pheochromocytoma](https://sugi.bio/atlas/disease/pheochromocytoma/), [Cowden syndrome 3](https://sugi.bio/atlas/disease/cowden-syndrome-3/), [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):** Carney-Stratakis syndrome, Cowden syndrome 3, Paragangliomas with sensorineural hearing loss, Pheochromocytoma, Hereditary cancer-predisposing syndrome, Hereditary pheochromocytoma and paraganglioma, PARAGANGLIOMA AND GASTROINTESTINAL STROMAL TUMOR, MAX-Related Hereditary Paraganglioma-Pheochromocytoma Syndrome, Tumor predisposition, Hereditary Cancer Syndrome.

## Same-residue context {#hotspot}

Residue **24** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [SDHD p.Pro24fs](/variant/sdhd-p-pro24fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related SDHD variant pages (same residue, condition, or type): [SDHD p.Pro24Leu](/variant/sdhd-p-pro24leu), [SDHD p.Pro24=](/variant/sdhd-p-pro24), [SDHD p.Pro24Ala](/variant/sdhd-p-pro24ala), [SDHD p.Pro24fs](/variant/sdhd-p-pro24fs), [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).

### 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 1473419). 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.*