# NM_001111.5(ADAR):c.1846G>T (p.Val616Phe)

https://sugi.bio/variant/adar-p-val616phe

## Summary

**ADAR p.Val616Phe (c.1846G>T)** is classified **Uncertain significance** in ADAR (ClinVar, Single submitter, 2 submitters; last evaluated 2021-10-27). AlphaMissense: likely pathogenic (0.732); Very rare (popmax 0.000169%, nfe); Associated with dyschromatosis symmetrica hereditaria.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs570647049 · 2 submitters · 2 linked conditions · AlphaMissense likely pathogenic · very rare (popmax 0.000169%, nfe)

## For patients & families {#patients}

This is a change in the ADAR gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 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.Val616Phe |
| Coding change (HGVS c.) | c.1846G>T |
| MANE Select transcript | [NM_001111](https://www.ncbi.nlm.nih.gov/nuccore/NM_001111) |
| dbSNP | [rs570647049](https://www.ncbi.nlm.nih.gov/snp/rs570647049/) |
| Variant type | single nucleotide variant |
| Location | chr1:154597916-154597916 (GRCh38) |
| ClinVar | [VCV1490210](https://www.ncbi.nlm.nih.gov/clinvar/variation/1490210/) |

**All HGVS expressions:** `LRG_1212:g.38645G>T`, `LRG_1212t1:c.1846G>T`, `NC_000001.10:g.154570392C>A`, `NC_000001.11:g.154597916C>A`, `NG_011844.2:g.38645G>T`, `NM_001025107.3:c.961G>T`, `NM_001111.4:c.1846G>T`, `NM_001111.5:c.1846G>T`, `NM_001193495.2:c.961G>T`, `NM_001365045.1:c.1873G>T`, `NM_001365046.1:c.961G>T`, `NM_001365047.1:c.961G>T`, `NM_001365048.1:c.961G>T`, `NM_001365049.1:c.961G>T`, `NM_015840.4:c.1846G>T`, `NM_015841.4:c.1846G>T`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **damaging** — a triage signal, not a reclassification.

- AlphaMissense **likely pathogenic** (0.732)
- REVEL 0.564 (indeterminate)
- SaProt LLR -12.401 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this damaging; REVEL makes no call
- Conservation: phyloP 5.932, GERP 1.84, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 25.6**. 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.*
- Regional missense constraint: **o/e 0.74** across the covering region of the MANE Select transcript (154,584,809–154,601,449), spanning 16,640 bp. Chi-square p 1.3e-17. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.000169%** (nfe) · FAF95 2.8e-05% · FAF99 1.1e-05% · 2/1,180,000 in the highest group · 2/1,461,872 alleles overall — very rare (popmax 0.000169%, nfe).

*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}

Residue **616** lies in the drbm 2 domain.

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. p.Val616Phe falls in the drbm 2 domain.


### 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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2021-10-27.

**Submitter consensus:** conflicting (1 Uncertain significance, 1 not provided).

**Submission history:** 2 submissions (2021); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-10-27 |
| GenomeConnect - Invitae Patient Insights Network | not provided | no classification provided | phenotyping only |  |

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

## Similar variants {#similar}

Related ADAR variant pages (same residue, condition, or type): [ADAR p.Val616Ile](/variant/adar-p-val616ile), [ADAR p.Val616=](/variant/adar-p-val616), [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).

### 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 1490210). 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.*