# NM_015107.3(PHF8):c.2318G>C (p.Arg773Pro)

https://sugi.bio/variant/phf8-p-arg773pro

## Summary

**PHF8 p.Arg773Pro (c.2318G>C)** is classified **Uncertain significance** in PHF8 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-06-09). AlphaMissense: ambiguous (0.404); Ultra-rare (popmax 0.023%, mid); Associated with Inborn genetic diseases.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs371107125 · 2 submitters · 2 linked conditions · AlphaMissense ambiguous · ultra-rare (popmax 0.023%, mid)

## For patients & families {#patients}

This is a change in the PHF8 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 submitters, and is linked to Inborn genetic diseases.

*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 | [PHF8](https://sugi.bio/atlas/gene/PHF8/) |
| Protein change (HGVS p.) | p.Arg773Pro |
| Coding change (HGVS c.) | c.2318G>C |
| MANE Select transcript | [NM_015107](https://www.ncbi.nlm.nih.gov/nuccore/NM_015107) |
| dbSNP | [rs371107125](https://www.ncbi.nlm.nih.gov/snp/rs371107125/) |
| Variant type | single nucleotide variant |
| Location | chrX:53985039-53985039 (GRCh38) |
| ClinVar | [VCV1804980](https://www.ncbi.nlm.nih.gov/clinvar/variation/1804980/) |

**All HGVS expressions:** `NC_000023.10:g.54011472C>G`, `NC_000023.11:g.53985039C>G`, `NG_021309.1:g.65098G>C`, `NM_001184896.1:c.2426G>C`, `NM_001184897.2:c.2015G>C`, `NM_001184898.2:c.2267G>C`, `NM_015107.3:c.2318G>C`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense makes no call; REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate — descriptive only.

- AlphaMissense **ambiguous** (0.404) — no call either way
- REVEL 0.12 (moderately benign-leaning)
- SaProt LLR -6.993 (tolerated)
- → **In-silico consensus:** REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate
- SpliceAI predicts **acceptor gain** (Δ 0.21) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 4.827, GERP 0.815, phastCons 1 — highly conserved
- ⚠ **Isoform check:** AlphaMissense is numbered on a different transcript (AM **R809P** vs ClinVar **R773P**) — the AlphaMissense read here may be for a different residue; verify against the ClinVar transcript.
- CADD: **PHRED 23.8**. 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 1.11** across the covering region of the MANE Select transcript (53,984,988–53,985,144), spanning 156 bp. Chi-square p 0.44. 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 **0.023%** (mid) · 1/4,353 in the highest group · 2/1,211,031 alleles overall — ultra-rare (popmax 0.023%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.023% | 4,353 |
| Remaining individuals (not grpmax-eligible) | 0.0021% | 47,637 |

*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}

**PHF8** population constraint: ClinGen dosage — haploinsufficiency 3/3, triplosensitivity 0/3. *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):

- **syndromic X-linked intellectual disability Siderius type** — Definitive (XL)

## Protein context {#protein}

Residue **809** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 63.30, 36% of residues very-high.

**6 experimental structure(s)** (PDB): [2WWU](https://www.rcsb.org/structure/2WWU), [3K3N](https://www.rcsb.org/structure/3K3N), [3K3O](https://www.rcsb.org/structure/3K3O), [3KV4](https://www.rcsb.org/structure/3KV4), [4DO0](https://www.rcsb.org/structure/4DO0), [7CMZ](https://www.rcsb.org/structure/7CMZ).

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

*Describes the biological roles of PHF8 (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:** PHF8's established molecular role includes chromatin binding. p.Arg773Pro falls in the disordered region.


### Pathways affected {#pathways}

PHF8 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [HDMs demethylate histones](https://reactome.org/content/detail/R-HSA-3214842) | curated |
| [Condensation of Prophase Chromosomes](https://reactome.org/content/detail/R-HSA-2299718) | other |

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

**Molecular function:** chromatin binding, iron ion binding, zinc ion binding, histone demethylase activity, histone H3K9 demethylase activity, histone H4K20 demethylase activity.

**Biological process:** G1/S transition of mitotic cell cycle, positive regulation of DNA-templated transcription, positive regulation of transcription by RNA polymerase I, positive regulation of transcription by RNA polymerase II, negative regulation of rDNA heterochromatin formation.

## Clinical significance {#significance}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-06-09.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2021–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-05-06 |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-06-09 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/), [syndromic X-linked intellectual disability Siderius type](https://sugi.bio/atlas/disease/syndromic-x-linked-intellectual-disability-siderius-type/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases, Syndromic X-linked intellectual disability Siderius type, INTELLECTUAL DEVELOPMENTAL DISORDER, X-LINKED, SYNDROMIC, SIDERIUS TYPE.

## Similar variants {#similar}

Related PHF8 variant pages (same residue, condition, or type): [PHF8 p.Arg773Cys](/variant/phf8-p-arg773cys), [PHF8 p.Arg773His](/variant/phf8-p-arg773his), [PHF8 p.Arg240Ter](/variant/phf8-p-arg240ter), [PHF8 p.Arg506Ter](/variant/phf8-p-arg506ter), [PHF8 p.Arg753Ter](/variant/phf8-p-arg753ter), [PHF8 p.Ala770Pro](/variant/phf8-p-ala770pro), [PHF8 p.Arg240Gln](/variant/phf8-p-arg240gln), [PHF8 p.Arg438His](/variant/phf8-p-arg438his).

### 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 1804980). 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.*