# NM_004168.4(SDHA):c.1663+3G>C

https://sugi.bio/variant/sdha-c-1663-plus-3g-c

## Summary

**SDHA c.1663+3G>C** is classified **Conflicting classifications of pathogenicity** in SDHA (ClinVar, Conflicting submitters, 9 submitters; last evaluated 2025-11-17). Very rare (popmax 0.00333%, amr); Associated with pheochromocytoma/paraganglioma syndrome 5.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs751904543 · 9 submitters · 4 linked conditions · very rare (popmax 0.00333%, amr)

## For patients & families {#patients}

This is a change in the SDHA gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 9 submitters, and is linked to pheochromocytoma/paraganglioma syndrome 5.

*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/0015763/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [SDHA](https://sugi.bio/atlas/gene/SDHA/) |
| Coding change (HGVS c.) | c.1663+3G>C |
| MANE Select transcript | [NM_004168](https://www.ncbi.nlm.nih.gov/nuccore/NM_004168) |
| dbSNP | [rs751904543](https://www.ncbi.nlm.nih.gov/snp/rs751904543/) |
| Variant type | single nucleotide variant |
| Location | chr5:251106-251106 (GRCh38) |
| ClinVar | [VCV577461](https://www.ncbi.nlm.nih.gov/clinvar/variation/577461/) |

**All HGVS expressions:** `LRG_315:g.37866G>C`, `LRG_315t1:c.1663+3G>C`, `NC_000005.10:g.251106G>C`, `NC_000005.9:g.251221G>C`, `NG_012339.1:g.37866G>C`, `NM_001294332.2:c.1519+3G>C`, `NM_001330758.2:c.1552-3287G>C`, `NM_004168.2:c.1663+3G>C`, `NM_004168.4:c.1663+3G>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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor loss** (Δ 0.53) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 1.533, GERP 0.322, phastCons 0.997 — weakly conserved position
- CADD: **PHRED 16.18**. 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.*
- Splice region: **donor splice region (+3, within the first 6 intronic nt)** — inside the zone ClinGen GN167 excludes from BP7, so this variant must not be called benign merely for being synonymous or intronic.
- Non-coding constraint (Gnocchi): **Z 2.75**, o/e 0.78 (1 kb window 251,000–252,000). A higher Z means the window carries less variation than expected. Describes the 1 kb window, not this allele. No ClinGen expert panel references Gnocchi and no ACMG-calibrated threshold exists for it. *Descriptive; no cut-point applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.53**, acceptor gain **0.00**, donor gain **0.03**. Largest is donor loss.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.53**, acceptor gain **0.00**, donor gain **0.03**.
- Pangolin: Δ**0.71** (loss), gain 0.01 / loss 0.71. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.00333%** (amr) · FAF95 0.000689% · FAF99 0.000539% · 2/60,000 in the highest group · 22/1,611,152 alleles overall — very rare (popmax 0.00333%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.00333% | 30,000 |
| Remaining individuals (not grpmax-eligible) | 0.00321% | 31,138 |
| East Asian | 0.00223% | 44,884 |
| South Asian | 0.0022% | 45,491 |
| African / African-American | 0.00134% | 74,832 |
| European (non-Finnish) | 0.00119% | 84,228 |

*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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2025-11-17.

**Submitter consensus:** conflicting (5 Likely pathogenic, 2 Uncertain significance, 1 Pathogenic, 1 likely pathogenic).

**Submission history:** 9 submissions (2021–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| “Giorgio Prodi” Cancer Research Center, University of Bologna | Uncertain significance | flagged submission | research | 2021-10-01 |
| Ambry Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-12-31 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-11-17 |
| Myriad Genetics, Inc. | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-02-08 |
| Clinical Genetics Laboratory, Skane University Hospital Lund | Likely pathogenic | criteria provided, single submitter | clinical testing | 2023-05-25 |
| PreventionGenetics, part of Exact Sciences | Likely pathogenic | no assertion criteria provided | clinical testing | 2024-03-08 |
| Quest Diagnostics Nichols Institute San Juan Capistrano | likely pathogenic | criteria provided, single submitter | clinical testing | 2024-09-11 |
| Clinical Genetics and Genomics, Karolinska University Hospital | Likely pathogenic | criteria provided, single submitter | clinical testing | 2025-02-17 |
| Blueprint Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-07-26 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Pheochromocytoma/paraganglioma syndrome 5, Mitochondrial complex II deficiency, nuclear type 1, Gastrointestinal stromal tumor, Hereditary cancer-predisposing syndrome, not provided, SDHA-related disorder, Paragangliomas 5, SDHA-Related Hereditary Paraganglioma-Pheochromocytoma Syndrome, none provided, Gastrointestinal stromal tumor, somatic.

## Similar variants {#similar}

Related SDHA variant pages (same residue, condition, or type): [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), [SDHA c.1260+2T>A](/variant/sdha-c-1260-plus-2t-a), [SDHA c.1261-1G>A](/variant/sdha-c-1261-minus-1g-a), [SDHA c.1261-2A>G](/variant/sdha-c-1261-minus-2a-g).

### 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 577461). 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.*