# NM_001111.5(ADAR):c.271del (p.Arg91fs)

https://sugi.bio/variant/adar-p-arg91fs

## Summary

**ADAR p.Arg91fs (c.271del)** is classified **Pathogenic** in ADAR (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-29). No gnomAD frequency available for this variant; Associated with dyschromatosis symmetrica hereditaria.

**At a glance:** Pathogenic · review: Single submitter · rsID rs2526669442 · 1 submitter · 2 linked conditions · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the ADAR gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, 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.Arg91fs |
| Coding change (HGVS c.) | c.271del |
| MANE Select transcript | [NM_001111](https://www.ncbi.nlm.nih.gov/nuccore/NM_001111) |
| dbSNP | [rs2526669442](https://www.ncbi.nlm.nih.gov/snp/rs2526669442/) |
| Variant type | Deletion |
| Location | chr1:154602371-154602371 (GRCh38) |
| ClinVar | [VCV2941916](https://www.ncbi.nlm.nih.gov/clinvar/variation/2941916/) |

**All HGVS expressions:** `LRG_1212:g.34190del`, `LRG_1212t1:c.271del`, `NC_000001.10:g.154574847del`, `NC_000001.11:g.154602371del`, `NG_011844.2:g.34190del`, `NM_001025107.3:c.-615del`, `NM_001111.5:c.271del`, `NM_001193495.2:c.-615del`, `NM_001365045.1:c.298del`, `NM_001365046.1:c.-493+14del`, `NM_001365047.1:c.-493+14del`, `NM_001365048.1:c.-615del`, `NM_001365049.1:c.-493+14del`, `NM_015840.4:c.271del`, `NM_015841.4:c.271del`

## 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 -2.05, GERP 1.69 — fast-evolving / accelerated position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. the gene is **loss-of-function-intolerant** (LOEUF 0.449, pLI 0.99972), supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 2 of 15**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — 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}

**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}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-11-29.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2022-11-29 |

## 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, RETICULATE ACROPIGMENTATION OF DOHI, SYMMETRIC DYSCHROMATOSIS OF THE EXTREMITIES, Dyschromatosis symmetrica hereditaria, DYSCHROMATOSIS SYMMETRICA HEREDITARIA 1.

## Similar variants {#similar}

Related ADAR variant pages (same residue, condition, or type): [ADAR p.Arg91Gly](/variant/adar-p-arg91gly), [ADAR p.Ala813fs](/variant/adar-p-ala813fs), [ADAR p.Ala220_Gly268del](/variant/adar-p-ala220-gly268del), [ADAR c.2886-11_2886-10del](/variant/adar-c-2886-minus-11-2886-minus-10del), [ADAR c.2886-1del](/variant/adar-c-2886-minus-1del), [ADAR p.Asn857fs](/variant/adar-p-asn857fs), [ADAR p.Asp342fs](/variant/adar-p-asp342fs), [ADAR p.Glu598fs](/variant/adar-p-glu598fs).

### 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 2941916). 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.*