# NM_003002.4(SDHD):c.64C>A (p.Arg22=)

https://sugi.bio/variant/sdhd-p-arg22

## Summary

**SDHD p.Arg22= (c.64C>A)** is classified **Uncertain significance** in SDHD (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-24). Very rare (popmax 0.00267%, afr); Associated with Carney-Stratakis syndrome.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs104894306 · 1 submitter · 3 linked conditions · very rare (popmax 0.00267%, afr)

## For patients & families {#patients}

This is a change in the SDHD gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, 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.Arg22= |
| Coding change (HGVS c.) | c.64C>A |
| MANE Select transcript | [NM_003002](https://www.ncbi.nlm.nih.gov/nuccore/NM_003002) |
| dbSNP | [rs104894306](https://www.ncbi.nlm.nih.gov/snp/rs104894306/) |
| Variant type | single nucleotide variant |
| Location | chr11:112087868-112087868 (GRCh38) |
| ClinVar | [VCV1055597](https://www.ncbi.nlm.nih.gov/clinvar/variation/1055597/) |

**All HGVS expressions:** `LRG_9:g.6022C>A`, `LRG_9t1:c.64C>A`, `NC_000011.10:g.112087868C>A`, `NC_000011.9:g.111958592C>A`, `NG_012337.3:g.6022C>A`, `NG_033145.1:g.3931G>T`, `NM_001276503.2:c.64C>A`, `NM_001276504.2:c.52+909C>A`, `NM_001276506.2:c.64C>A`, `NM_003002.4:c.64C>A`, `NR_077060.2:n.99C>A`

## 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 **acceptor loss** (Δ 0.30) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 1.71, GERP 1.08, phastCons 0.005 — weakly conserved position
- CADD: **PHRED 5.451**. 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 deltas (raw): acceptor loss **0.30**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**. Largest is acceptor loss, 11 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Pangolin: Δ**0.32** (loss), gain 0.01 / loss 0.32. 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 **0.00267%** (afr) · FAF95 0.000443% · FAF99 0.000166% · 2/75,012 in the highest group · 2/1,611,878 alleles overall — very rare (popmax 0.00267%, afr).

*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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-12-24.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-12-24 |

## 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/).

**Reported phenotype names (ClinVar):** Carney-Stratakis syndrome, Cowden syndrome 3, Paragangliomas with sensorineural hearing loss, Pheochromocytoma, PARAGANGLIOMA AND GASTROINTESTINAL STROMAL TUMOR, MAX-Related Hereditary Paraganglioma-Pheochromocytoma Syndrome.

## Same-residue context {#hotspot}

Residue **22** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [SDHD p.Arg22Ter](/variant/sdhd-p-arg22ter). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related SDHD variant pages (same residue, condition, or type): [SDHD p.Arg22Ter](/variant/sdhd-p-arg22ter), [SDHD p.Arg22Gln](/variant/sdhd-p-arg22gln), [SDHD p.Arg22Pro](/variant/sdhd-p-arg22pro), [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).

### 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 1055597). 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.*