# NM_025000.4(DCAF17):c.959G>T (p.Cys320Phe)

https://sugi.bio/variant/dcaf17-p-cys320phe

## Summary

**DCAF17 p.Cys320Phe (c.959G>T)** is classified **Uncertain significance** in DCAF17 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-13). AlphaMissense: likely benign (0.2427); Absent from gnomAD v4.1; Associated with Woodhouse-Sakati syndrome.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs1696082466 · 1 submitter · 1 linked condition · AlphaMissense likely benign · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the DCAF17 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to Woodhouse-Sakati 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 recessive |
| Age of onset (of this condition) | Adolescent, Childhood |
| Clinical trials | 1 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | DCAF17 is a diagnostic-grade gene on 12 Genomics England panels |

**Commonly reported features of Woodhouse-Sakati syndrome** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Hypoplasia of the uterus — Very frequent (99-80%)
- Micropenis — Very frequent (99-80%)
- Hypogonadism — Very frequent (99-80%)
- Protruding ear — Very frequent (99-80%)
- Hypothyroidism — Very frequent (99-80%)
- Delayed puberty — Very frequent (99-80%)
- Decreased response to growth hormone stimulation test — Very frequent (99-80%)
- Insulin-resistant diabetes mellitus — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0005592/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [DCAF17](https://sugi.bio/atlas/gene/DCAF17/) |
| Protein change (HGVS p.) | p.Cys320Phe |
| Coding change (HGVS c.) | c.959G>T |
| MANE Select transcript | [NM_025000](https://www.ncbi.nlm.nih.gov/nuccore/NM_025000) |
| dbSNP | [rs1696082466](https://www.ncbi.nlm.nih.gov/snp/rs1696082466/) |
| Variant type | single nucleotide variant |
| Location | chr2:171469008-171469008 (GRCh38) |
| ClinVar | [VCV893041](https://www.ncbi.nlm.nih.gov/clinvar/variation/893041/) |

**All HGVS expressions:** `NC_000002.11:g.172325518G>T`, `NC_000002.12:g.171469008G>T`, `NG_013038.2:g.39758G>T`, `NM_001164821.2:c.959G>T`, `NM_025000.4:c.959G>T`, `NR_028482.2:n.1205G>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.2427)
- REVEL 0.405 (indeterminate)
- SaProt LLR -8.565 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate
- Conservation: phyloP 11.844, GERP 1.69, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 27.7**. 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 0.36** across the covering region of the MANE Select transcript (171,468,920–171,469,009), spanning 89 bp. Chi-square p 0.00015. 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: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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}

**DCAF17** population constraint: LOEUF 0.855, pLI 3.4768e-07, missense-Z 0.92354. *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):

- **Woodhouse-Sakati syndrome** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 87.38, 65% of residues very-high.

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

*Describes the biological roles of DCAF17 (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}

DCAF17 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Neddylation](https://reactome.org/content/detail/R-HSA-8951664) | curated |

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2018-01-13.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Illumina Laboratory Services, Illumina | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-01-13 |

## Associated conditions {#conditions}

[Woodhouse-Sakati syndrome](https://sugi.bio/atlas/disease/woodhouse-sakati-syndrome/).

**Reported phenotype names (ClinVar):** Woodhouse-Sakati syndrome, Hypogonadism, Alopecia, Diabetes Mellitus, Mental Retardation, and Extrapyramidal Syndrome, Hypogonadism, diabetes mellitus, alopecia, mental retardation and electrocardiographic abnormalities, EXTRAPYRAMIDAL DISORDER, PROGRESSIVE, WITH PRIMARY HYPOGONADISM, MENTAL RETARDATION, AND ALOPECIA.

## Similar variants {#similar}

Related DCAF17 variant pages (same residue, condition, or type): [DCAF17 c.127-1G>C](/variant/dcaf17-c-127-minus-1g-c), [DCAF17 p.Arg194Ter](/variant/dcaf17-p-arg194ter), [DCAF17 p.Met1Val](/variant/dcaf17-p-met1val), [DCAF17 p.Trp129Ter](/variant/dcaf17-p-trp129ter), [DCAF17 p.Trp302Ter](/variant/dcaf17-p-trp302ter), [DCAF17 c.1266+4T>C](/variant/dcaf17-c-1266-plus-4t-c), [DCAF17 c.*126A>T](/variant/dcaf17-c-star-126a-t), [DCAF17 p.Ala242Thr](/variant/dcaf17-p-ala242thr).

### 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 893041). 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.*