# NM_001111.5(ADAR):c.30C>T (p.Ser10=)

https://sugi.bio/variant/adar-p-ser10

## Summary

**ADAR p.Ser10= (c.30C>T)** is classified **Likely benign** in ADAR (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-02-17). Ultra-rare (popmax 0.069%, eas); Associated with dyschromatosis symmetrica hereditaria.

**At a glance:** Likely benign · review: Multiple submitters · rsID rs769752403 · 3 submitters · 2 linked conditions · ultra-rare (popmax 0.069%, eas)

## For patients & families {#patients}

This is a change in the ADAR gene that is classified as likely benign — not considered disease-causing, submitted by 3 submitters, and is linked to dyschromatosis symmetrica hereditaria.

*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) | Childhood |
| Clinical trials | 1 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | ADAR is a diagnostic-grade gene on 23 Genomics England panels |

**Commonly reported features of Dyschromatosis symmetrica hereditaria** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Macular hypopigmentation — Very frequent (99-80%)
- Macular hyperpigmentation — Very frequent (99-80%)
- Macule — Very frequent (99-80%)
- Torsion dystonia — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0000334/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ADAR](https://sugi.bio/atlas/gene/ADAR/) |
| Protein change (HGVS p.) | p.Ser10= |
| Coding change (HGVS c.) | c.30C>T |
| MANE Select transcript | [NM_001111](https://www.ncbi.nlm.nih.gov/nuccore/NM_001111) |
| dbSNP | [rs769752403](https://www.ncbi.nlm.nih.gov/snp/rs769752403/) |
| Variant type | single nucleotide variant |
| Location | chr1:154602612-154602612 (GRCh38) |
| ClinVar | [VCV1131547](https://www.ncbi.nlm.nih.gov/clinvar/variation/1131547/) |

**All HGVS expressions:** `LRG_1212:g.33949C>T`, `LRG_1212t1:c.30C>T`, `NC_000001.10:g.154575088G>A`, `NC_000001.11:g.154602612G>A`, `NG_011844.2:g.33949C>T`, `NM_001025107.3:c.-856C>T`, `NM_001111.5:c.30C>T`, `NM_001193495.2:c.-856C>T`, `NM_001365045.1:c.57C>T`, `NM_001365046.1:c.-720C>T`, `NM_001365047.1:c.-720C>T`, `NM_001365048.1:c.-856C>T`, `NM_001365049.1:c.-720C>T`, `NM_015840.4:c.30C>T`, `NM_015841.4:c.30C>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 1.168, GERP 0.579, phastCons 0.001 — weakly conserved position
- CADD: **PHRED 3.956**. 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 (G>C, Δ0.26 acceptor loss), 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 (gnomAD v4.1): grpmax **0.069%** (eas) · FAF95 0.05% · FAF99 0.0434% · 31/44,896 in the highest group · 80/1,614,020 alleles overall — ultra-rare (popmax 0.069%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.069% | 1,448 |
| South Asian | 0.045% | 2,221 |
| Middle Eastern | 0.0335% | 2,987 |
| Remaining individuals (not grpmax-eligible) | 0.0032% | 31,250 |
| Finnish (not grpmax-eligible) | 0.00156% | 63,928 |
| European (non-Finnish) | 0.000254% | 393,342 |

*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}

**ADAR** population constraint: LOEUF 0.449, pLI 0.99972, missense-Z 3.4201. *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):

- **Leigh syndrome** — Limited (AR)
- **ADAR-related type 1 interferonopathy** — Definitive (AR)
- **ADAR-related type 1 interferonopathy** — Definitive (AD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 68.86, 35% of residues very-high.

**24 experimental structure(s)** (PDB): [1QBJ](https://www.rcsb.org/structure/1QBJ), [1QGP](https://www.rcsb.org/structure/1QGP), [1XMK](https://www.rcsb.org/structure/1XMK), [2ACJ](https://www.rcsb.org/structure/2ACJ), [2GXB](https://www.rcsb.org/structure/2GXB), [2L54](https://www.rcsb.org/structure/2L54) — incl. mutant structure 2L54.

## What this gene does {#gene-function}

*Describes the biological roles of ADAR (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:** ADAR's established molecular role includes RNA binding.


### Pathways affected {#pathways}

ADAR participates in **4 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [C6 deamination of adenosine](https://reactome.org/content/detail/R-HSA-75102) | curated |
| [Formation of editosomes by ADAR proteins](https://reactome.org/content/detail/R-HSA-77042) | curated |
| [Interferon alpha/beta signaling](https://reactome.org/content/detail/R-HSA-909733) | curated |
| [PKR-mediated signaling](https://reactome.org/content/detail/R-HSA-9833482) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** RNA binding, double-stranded RNA adenosine deaminase activity.

**Biological process:** adenosine to inosine editing, protein import into nucleus, protein export from nucleus, response to virus, base conversion or substitution editing, mRNA modification.

## Clinical significance {#significance}

**Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-02-17.

**Submitter consensus:** unanimous (3/3 Likely benign).

**Submission history:** 3 submissions (2023–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-02-17 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2024-02-01 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2023-12-14 |

## Associated conditions {#conditions}

[dyschromatosis symmetrica hereditaria](https://sugi.bio/atlas/disease/dyschromatosis-symmetrica-hereditaria/), [Aicardi-Goutieres syndrome 6](https://sugi.bio/atlas/disease/aicardi-goutieres-syndrome-6/).

**Reported phenotype names (ClinVar):** Symmetrical dyschromatosis of extremities, Aicardi-Goutieres syndrome 6, not provided, not specified, DYSCHROMATOSIS SYMMETRICA HEREDITARIA 1, RETICULATE ACROPIGMENTATION OF DOHI, SYMMETRIC DYSCHROMATOSIS OF THE EXTREMITIES, Dyschromatosis symmetrica hereditaria, none provided, AllHighlyPenetrant.

## Similar variants {#similar}

Related ADAR variant pages (same residue, condition, or type): [ADAR c.2885+1G>A](/variant/adar-c-2885-plus-1g-a), [ADAR p.Arg1078Cys](/variant/adar-p-arg1078cys), [ADAR p.Arg1096Ter](/variant/adar-p-arg1096ter), [ADAR p.Arg328Ter](/variant/adar-p-arg328ter), [ADAR p.Arg360Ter](/variant/adar-p-arg360ter), [ADAR p.Arg474Ter](/variant/adar-p-arg474ter), [ADAR p.Gln559Ter](/variant/adar-p-gln559ter), [ADAR p.Lys1122Gln](/variant/adar-p-lys1122gln).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); 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 2026-07-14); 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 1131547). 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.*