# NM_004168.4(SDHA):c.1827C>T (p.Pro609=)

https://sugi.bio/variant/sdha-p-pro609

## Summary

**SDHA p.Pro609= (c.1827C>T)** is classified **Likely benign** in SDHA (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-09). No allele count reported in gnomAD v4.1 (AN 1,603,282); Associated with mitochondrial complex II deficiency, nuclear type 1.

**At a glance:** Likely benign · review: Multiple submitters · rsID rs1060505006 · 2 submitters · 3 linked conditions · no allele count reported in gnomAD v4.1 (AN 1,603,282)

## For patients & families {#patients}

This is a change in the SDHA gene that is classified as likely benign — not considered disease-causing, submitted by 2 submitters, and is linked to mitochondrial complex II deficiency, nuclear type 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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Age of onset (of this condition) | Infancy, Neonatal |
| Diagnostic panels | SDHA is a diagnostic-grade gene on 18 Genomics England panels |

**Commonly reported features of Isolated succinate-CoQ reductase deficiency** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Abnormality of the eye — Frequent (79-30%)
- Spasticity — Frequent (79-30%)
- Motor delay — Frequent (79-30%)
- Abnormality of the cardiovascular system — Frequent (79-30%)
- Hypertrophic cardiomyopathy — Frequent (79-30%)
- Left ventricular hypertrophy — Frequent (79-30%)
- Weight loss — Frequent (79-30%)
- Generalized myoclonic seizure — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0005053/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [SDHA](https://sugi.bio/atlas/gene/SDHA/) |
| Protein change (HGVS p.) | p.Pro609= |
| Coding change (HGVS c.) | c.1827C>T |
| MANE Select transcript | [NM_004168](https://www.ncbi.nlm.nih.gov/nuccore/NM_004168) |
| dbSNP | [rs1060505006](https://www.ncbi.nlm.nih.gov/snp/rs1060505006/) |
| Variant type | single nucleotide variant |
| Location | chr5:254425-254425 (GRCh38) |
| ClinVar | [VCV1082078](https://www.ncbi.nlm.nih.gov/clinvar/variation/1082078/) |

**All HGVS expressions:** `LRG_315:g.41185C>T`, `LRG_315t1:c.1827C>T`, `NC_000005.10:g.254425C>T`, `NC_000005.9:g.254540C>T`, `NG_012339.1:g.41185C>T`, `NM_001294332.2:c.1683C>T`, `NM_001330758.2:c.1584C>T`, `NM_004168.2:c.1827C>T`, `NM_004168.4:c.1827C>T`

## 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 0.014, GERP 1.67, phastCons 0.001 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 10.46**. 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: **no splice effect predicted**. SpliceAI outputs four numbers per variant, not one: acceptor loss, donor loss, acceptor gain, donor gain (DS_AL / DS_DL / DS_AG / DS_DG). A loss score is an existing splice site weakened or destroyed; a gain score is a new site created or an existing one strengthened. The release publishes its own filter rule, which we read from the dataset rather than assume: an allele is reported only if the largest of its four deltas reaches 0.2. No allele at this position is in the release, so all four are under 0.2 for every alternate allele here. No figure is shown because none was read: the bound is deduced from that absence. It is a result, not a gap in our data, because the release scores every possible substitution across the transcripts it covers (Ensembl MANE v1.4) before it filters, so what survives for a gene is one continuous stretch. What is measured is that this position sits inside the stretch covered for SDHA (1,028 scored positions, the nearest 3 bases away); what is taken from the release's own description, rather than measured, is that coverage inside that stretch is continuous. On that, SpliceAI did score it. *ClinGen's SVI treats the largest of the four as evidence against a splicing effect at or below 0.1, where it may support BP4, and as uninformative between 0.1 and 0.2. We cannot tell which applies here, so these SpliceAI data support neither BP4 nor PP3; that is a statement about this evidence alone, not about the variant's other evidence.*
- Population frequency: **no allele count reported in gnomAD v4.1 (AN 1,603,282)** — 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}

**SDHA** population constraint: LOEUF 0.786, pLI 3.3694e-08, missense-Z 2.306. *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):

- **hereditary pheochromocytoma-paraganglioma** — Definitive (AD)
- **Leigh syndrome** — Moderate (AR)
- **mitochondrial disease** — Definitive (AR)
- **mitochondrial disease** — Limited (AD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 94.06, 92% of residues very-high.

**5 experimental structure(s)** (PDB): [6VAX](https://www.rcsb.org/structure/6VAX), [8DYD](https://www.rcsb.org/structure/8DYD), [8DYE](https://www.rcsb.org/structure/8DYE), [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 SDHA (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:** SDHA's established molecular role includes succinate dehydrogenase (quinone) activity.


### Pathways affected {#pathways}

SDHA 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.

**Biological process:** succinate metabolic process, nervous system development, respiratory electron transport chain.

## Clinical significance {#significance}

**Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-08-09.

**Submitter consensus:** unanimous (2/2 Likely benign).

**Submission history:** 2 submissions (2020–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2025-08-09 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2020-08-01 |

## Associated conditions {#conditions}

[mitochondrial complex II deficiency, nuclear type 1](https://sugi.bio/atlas/disease/mitochondrial-complex-ii-deficiency-nuclear-type-1/), [pheochromocytoma/paraganglioma syndrome 5](https://sugi.bio/atlas/disease/pheochromocytoma-paraganglioma-syndrome-5/), [hereditary neoplastic syndrome](https://sugi.bio/atlas/disease/hereditary-neoplastic-syndrome/).

**Reported phenotype names (ClinVar):** Mitochondrial complex II deficiency, nuclear type 1, Pheochromocytoma/paraganglioma syndrome 5, Hereditary cancer-predisposing syndrome, SUCCINATE CoQ REDUCTASE DEFICIENCY, Paragangliomas 5, SDHA-Related Hereditary Paraganglioma-Pheochromocytoma Syndrome, Tumor predisposition, Hereditary neoplastic syndrome, Neoplastic Syndromes, Hereditary, Hereditary Cancer Syndrome.

## Similar variants {#similar}

Related SDHA variant pages (same residue, condition, or type): [SDHA p.Pro609Ser](/variant/sdha-p-pro609ser), [SDHA p.Pro609Arg](/variant/sdha-p-pro609arg), [SDHA p.Pro609Leu](/variant/sdha-p-pro609leu), [SDHA c.1064+1G>A](/variant/sdha-c-1064-plus-1g-a), [SDHA c.1064+1G>T](/variant/sdha-c-1064-plus-1g-t), [SDHA c.1064+2T>A](/variant/sdha-c-1064-plus-2t-a), [SDHA c.1065-2A>G](/variant/sdha-c-1065-minus-2a-g), [SDHA c.1260+1G>T](/variant/sdha-c-1260-plus-1g-t).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 1082078). 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.*