# NM_007002.4(ADRM1):c.668C>T (p.Ser223Phe)

https://sugi.bio/variant/adrm1-p-ser223phe

## Summary

**ADRM1 p.Ser223Phe (c.668C>T)** is classified **Uncertain significance** in ADRM1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-17). AlphaMissense: likely benign (0.1467); Very rare (popmax 0.00668%, eas).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs1985276320 · 1 submitter · AlphaMissense likely benign · very rare (popmax 0.00668%, eas)

## For patients & families {#patients}

This is a change in the ADRM1 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter.

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

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ADRM1](https://sugi.bio/atlas/gene/ADRM1/) |
| Protein change (HGVS p.) | p.Ser223Phe |
| Coding change (HGVS c.) | c.668C>T |
| MANE Select transcript | [NM_007002](https://www.ncbi.nlm.nih.gov/nuccore/NM_007002) |
| dbSNP | [rs1985276320](https://www.ncbi.nlm.nih.gov/snp/rs1985276320/) |
| Variant type | single nucleotide variant |
| Location | chr20:62307640-62307640 (GRCh38) |
| ClinVar | [VCV2547717](https://www.ncbi.nlm.nih.gov/clinvar/variation/2547717/) |

**All HGVS expressions:** `NC_000020.10:g.60882696C>T`, `NC_000020.11:g.62307640C>T`, `NG_050626.1:g.64681G>A`, `NG_050626.2:g.64672G>A`, `NG_050661.1:g.10585C>T`, `NG_050661.2:g.9746C>T`, `NM_001281437.1:c.551C>T`, `NM_001281438.1:c.551C>T`, `NM_007002.4:c.668C>T`, `NM_175573.2:c.668C>T`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely benign** (0.1467)
- REVEL 0.097 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -12.861 (damaging) — differs from AlphaMissense
- → **In-silico consensus:** SaProt calls this damaging; AlphaMissense and REVEL do not
- SpliceAI predicts **acceptor gain** (Δ 0.21) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 7.598, GERP 1.56, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 28.7**. 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 0.88** across the covering region of the MANE Select transcript (62,303,753–62,308,758), spanning 5,005 bp. Chi-square p 0.0094. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.21**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.21**, donor gain **0.00**.
- Population frequency (gnomAD v4.1): grpmax **0.00668%** (eas) · FAF95 0.00177% · FAF99 0.000891% · 3/44,892 in the highest group · 3/1,612,018 alleles overall — very rare (popmax 0.00668%, eas).

*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}

**ADRM1** population constraint: LOEUF 0.188, pLI 1, missense-Z 1.24. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **223** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 64.34, 19% of residues very-high.

**21 experimental structure(s)** (PDB): [2KQZ](https://www.rcsb.org/structure/2KQZ), [2KR0](https://www.rcsb.org/structure/2KR0), [2L5V](https://www.rcsb.org/structure/2L5V), [2MKZ](https://www.rcsb.org/structure/2MKZ), [2NBV](https://www.rcsb.org/structure/2NBV), [4UEL](https://www.rcsb.org/structure/4UEL).

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

*Describes the biological roles of ADRM1 (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:** ADRM1's established molecular role includes protease binding. p.Ser223Phe falls in the disordered region. In Reactome, ADRM1 is annotated in disease pathway(s) including **Defective CFTR causes cystic fibrosis**, **Hh mutants are degraded by ERAD**.

**Disease mechanism (Reactome):** ADRM1 loss or alteration is curated in [Defective CFTR causes cystic fibrosis](https://reactome.org/content/detail/R-HSA-5678895), [Hh mutants are degraded by ERAD](https://reactome.org/content/detail/R-HSA-5362768), [Vif-mediated degradation of APOBEC3G](https://reactome.org/content/detail/R-HSA-180585).

### Pathways affected {#pathways}

ADRM1 participates in **68 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective CFTR causes cystic fibrosis](https://reactome.org/content/detail/R-HSA-5678895) | curated |
| ⚕ [Hh mutants are degraded by ERAD](https://reactome.org/content/detail/R-HSA-5362768) | curated |
| ⚕ [Vif-mediated degradation of APOBEC3G](https://reactome.org/content/detail/R-HSA-180585) | curated |
| ⚕ [Vpu mediated degradation of CD4](https://reactome.org/content/detail/R-HSA-180534) | curated |
| [ABC-family protein mediated transport](https://reactome.org/content/detail/R-HSA-382556) | curated |
| [AMPK-induced ERAD and lysosome mediated degradation of PD-L1(CD274)](https://reactome.org/content/detail/R-HSA-9931269) | curated |
| [APC/C:Cdc20 mediated degradation of Securin](https://reactome.org/content/detail/R-HSA-174154) | curated |
| [APC/C:Cdh1 mediated degradation of Cdc20 and other APC/C:Cdh1 targeted proteins in late mitosis/early G1](https://reactome.org/content/detail/R-HSA-174178) | curated |
| [AUF1 (hnRNP D0) binds and destabilizes mRNA](https://reactome.org/content/detail/R-HSA-450408) | curated |
| [Activation of NF-kappaB in B cells](https://reactome.org/content/detail/R-HSA-1169091) | curated |
| [Antigen processing: Ubiquitination & Proteasome degradation](https://reactome.org/content/detail/R-HSA-983168) | curated |
| [Assembly of the pre-replicative complex](https://reactome.org/content/detail/R-HSA-68867) | curated |
| [Asymmetric localization of PCP proteins](https://reactome.org/content/detail/R-HSA-4608870) | curated |
| [Autodegradation of Cdh1 by Cdh1:APC/C](https://reactome.org/content/detail/R-HSA-174084) | curated |
| [Autodegradation of the E3 ubiquitin ligase COP1](https://reactome.org/content/detail/R-HSA-349425) | curated |
| [CDK-mediated phosphorylation and removal of Cdc6](https://reactome.org/content/detail/R-HSA-69017) | curated |
| [CLEC7A (Dectin-1) signaling](https://reactome.org/content/detail/R-HSA-5607764) | curated |
| [Cdc20:Phospho-APC/C mediated degradation of Cyclin A](https://reactome.org/content/detail/R-HSA-174184) | curated |
| [Cross-presentation of soluble exogenous antigens (endosomes)](https://reactome.org/content/detail/R-HSA-1236978) | curated |
| [Dectin-1 mediated noncanonical NF-kB signaling](https://reactome.org/content/detail/R-HSA-5607761) | curated |
| [Degradation of AXIN](https://reactome.org/content/detail/R-HSA-4641257) | curated |
| [Degradation of CDH1](https://reactome.org/content/detail/R-HSA-9766229) | curated |
| [Degradation of DVL](https://reactome.org/content/detail/R-HSA-4641258) | curated |
| [Degradation of GLI1 by the proteasome](https://reactome.org/content/detail/R-HSA-5610780) | curated |
| [Degradation of beta-catenin by the destruction complex](https://reactome.org/content/detail/R-HSA-195253) | curated |
| [Downstream TCR signaling](https://reactome.org/content/detail/R-HSA-202424) | curated |
| [FBXL7 down-regulates AURKA during mitotic entry and in early mitosis](https://reactome.org/content/detail/R-HSA-8854050) | curated |
| [FCERI mediated NF-kB activation](https://reactome.org/content/detail/R-HSA-2871837) | curated |
| [G2/M Checkpoints](https://reactome.org/content/detail/R-HSA-69481) | curated |
| [GLI3 is processed to GLI3R by the proteasome](https://reactome.org/content/detail/R-HSA-5610785) | curated |
| [GSK3B and BTRC:CUL1-mediated-degradation of NFE2L2](https://reactome.org/content/detail/R-HSA-9762114) | curated |
| [GSK3B-mediated proteasomal degradation of PD-L1(CD274)](https://reactome.org/content/detail/R-HSA-9929356) | curated |
| [Hedgehog 'on' state](https://reactome.org/content/detail/R-HSA-5632684) | curated |
| [Hedgehog ligand biogenesis](https://reactome.org/content/detail/R-HSA-5358346) | curated |
| [Interleukin-1 signaling](https://reactome.org/content/detail/R-HSA-9020702) | curated |
| [KEAP1-NFE2L2 pathway](https://reactome.org/content/detail/R-HSA-9755511) | curated |
| [MAPK6/MAPK4 signaling](https://reactome.org/content/detail/R-HSA-5687128) | curated |
| [NIK-->noncanonical NF-kB signaling](https://reactome.org/content/detail/R-HSA-5676590) | curated |
| [Neddylation](https://reactome.org/content/detail/R-HSA-8951664) | curated |
| [Negative Regulation of DNA Double Strand Break Response](https://reactome.org/content/detail/R-HSA-9974237) | curated |
| [Orc1 removal from chromatin](https://reactome.org/content/detail/R-HSA-68949) | curated |
| [Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha](https://reactome.org/content/detail/R-HSA-1234176) | curated |
| [RUNX1 regulates transcription of genes involved in differentiation of HSCs](https://reactome.org/content/detail/R-HSA-8939236) | curated |
| [Regulation of PTEN stability and activity](https://reactome.org/content/detail/R-HSA-8948751) | curated |
| [Regulation of RAS by GAPs](https://reactome.org/content/detail/R-HSA-5658442) | curated |
| [Regulation of RUNX3 expression and activity](https://reactome.org/content/detail/R-HSA-8941858) | curated |
| [Regulation of ornithine decarboxylase (ODC)](https://reactome.org/content/detail/R-HSA-350562) | curated |
| [SCF(Skp2)-mediated degradation of p27/p21](https://reactome.org/content/detail/R-HSA-187577) | curated |
| [SCF-beta-TrCP mediated degradation of Emi1](https://reactome.org/content/detail/R-HSA-174113) | curated |
| [SPOP-mediated proteasomal degradation of PD-L1(CD274)](https://reactome.org/content/detail/R-HSA-9929491) | curated |
| [Separation of Sister Chromatids](https://reactome.org/content/detail/R-HSA-2467813) | curated |
| [TNFR2 non-canonical NF-kB pathway](https://reactome.org/content/detail/R-HSA-5668541) | curated |
| [The role of GTSE1 in G2/M progression after G2 checkpoint](https://reactome.org/content/detail/R-HSA-8852276) | curated |
| [UCH proteinases](https://reactome.org/content/detail/R-HSA-5689603) | curated |
| [Ub-specific processing proteases](https://reactome.org/content/detail/R-HSA-5689880) | curated |
| [Ubiquitin-Mediated Degradation of Phosphorylated Cdc25A](https://reactome.org/content/detail/R-HSA-69601) | curated |
| [Ubiquitin-dependent degradation of Cyclin D](https://reactome.org/content/detail/R-HSA-75815) | curated |
| [Activation of STAT3 by cadherin engagement](https://reactome.org/content/detail/R-HSA-9958825) | electronic |
| [Degradation of CRY and PER proteins](https://reactome.org/content/detail/R-HSA-9932298) | electronic |
| [Degradation of GLI2 by the proteasome](https://reactome.org/content/detail/R-HSA-5610783) | electronic |
| [ER-Phagosome pathway](https://reactome.org/content/detail/R-HSA-1236974) | electronic |
| [Negative regulation of NOTCH4 signaling](https://reactome.org/content/detail/R-HSA-9604323) | electronic |
| [Proteasome assembly](https://reactome.org/content/detail/R-HSA-9907900) | electronic |
| [Regulation of RUNX2 expression and activity](https://reactome.org/content/detail/R-HSA-8939902) | electronic |
| [Regulation of activated PAK-2p34 by proteasome mediated degradation](https://reactome.org/content/detail/R-HSA-211733) | electronic |
| [Regulation of expression of SLITs and ROBOs](https://reactome.org/content/detail/R-HSA-9010553) | electronic |
| [Ribosome Quality Control (RQC) complex extracts and degrades nascent peptide](https://reactome.org/content/detail/R-HSA-9954709) | electronic |
| [Somitogenesis](https://reactome.org/content/detail/R-HSA-9824272) | electronic |

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

**Molecular function:** protease binding, endopeptidase activator activity, proteasome binding, molecular function inhibitor activity.

**Biological process:** transcription elongation by RNA polymerase II, proteasome assembly.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-05-17.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-05-17 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related ADRM1 variant pages (same residue, condition, or type): [ADRM1 p.Ala245=](/variant/adrm1-p-ala245), [ADRM1 p.Ala324Val](/variant/adrm1-p-ala324val), [ADRM1 p.Asp266=](/variant/adrm1-p-asp266), [ADRM1 p.Pro315=](/variant/adrm1-p-pro315), [ADRM1 p.Ala149Gly](/variant/adrm1-p-ala149gly), [ADRM1 p.Ala236Thr](/variant/adrm1-p-ala236thr), [ADRM1 p.Ala239Thr](/variant/adrm1-p-ala239thr), [ADRM1 p.Ala245Thr](/variant/adrm1-p-ala245thr).

### 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 2547717). 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.*