# NM_005392.4(PHF2):c.2421C>T (p.Ser807=)

https://sugi.bio/variant/phf2-p-ser807

## Summary

**PHF2 p.Ser807= (c.2421C>T)** is classified **Likely benign** in PHF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2017-09-20). Ultra-rare (popmax 0.0335%, mid).

**At a glance:** Likely benign · review: Single submitter · rsID rs199537702 · 1 submitter · ultra-rare (popmax 0.0335%, mid)

## For patients & families {#patients}

This is a change in the PHF2 gene that is classified as likely benign — not considered disease-causing, 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 | [PHF2](https://sugi.bio/atlas/gene/PHF2/) |
| Protein change (HGVS p.) | p.Ser807= |
| Coding change (HGVS c.) | c.2421C>T |
| MANE Select transcript | [NM_005392](https://www.ncbi.nlm.nih.gov/nuccore/NM_005392) |
| dbSNP | [rs199537702](https://www.ncbi.nlm.nih.gov/snp/rs199537702/) |
| Variant type | single nucleotide variant |
| Location | chr9:93673657-93673657 (GRCh38) |
| ClinVar | [VCV778436](https://www.ncbi.nlm.nih.gov/clinvar/variation/778436/) |

**All HGVS expressions:** `NC_000009.11:g.96435939C>T`, `NC_000009.12:g.93673657C>T`, `NG_047001.1:g.102031C>T`, `NM_005392.4:c.2421C>T`

## 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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **acceptor gain** (Δ 0.35) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP -2.338, GERP -3.8 — fast-evolving / accelerated position
- CADD: **PHRED 16.37**. 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.*
- SpliceAI deltas (raw): acceptor loss **0.04**, donor loss **0.00**, acceptor gain **0.35**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.35**, donor gain **0.00**.
- Population frequency (gnomAD v4.1): grpmax **0.0335%** (mid) · FAF95 0.0102% · FAF99 0.00873% · 2/5,962 in the highest group · 334/1,610,854 alleles overall — ultra-rare (popmax 0.0335%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Ashkenazi Jewish (not grpmax-eligible) | 0.484% | 207 |
| Remaining individuals (not grpmax-eligible) | 0.0417% | 2,397 |
| Middle Eastern (grpmax) | 0.0335% | 2,981 |
| African / African-American | 0.0173% | 5,770 |
| South Asian | 0.0165% | 6,060 |
| Admixed American | 0.0117% | 8,559 |
| European (non-Finnish) | 0.0109% | 9,205 |

Ashkenazi Jewish shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}

**PHF2** population constraint: LOEUF 0.329, pLI 1, missense-Z 3.5968; ClinGen dosage — haploinsufficiency 1/3, triplosensitivity 0/3. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 62.14, 34% of residues very-high.

**9 experimental structure(s)** (PDB): [3KQI](https://www.rcsb.org/structure/3KQI), [3PTR](https://www.rcsb.org/structure/3PTR), [3PU3](https://www.rcsb.org/structure/3PU3), [3PU8](https://www.rcsb.org/structure/3PU8), [3PUA](https://www.rcsb.org/structure/3PUA), [3PUS](https://www.rcsb.org/structure/3PUS).

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

*Describes the biological roles of PHF2 (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:** PHF2's established molecular role includes transcription coactivator activity.


### Pathways affected {#pathways}

PHF2 participates in **1 Reactome pathway** (⚕ = disease pathway):

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

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

**Molecular function:** transcription coactivator activity, iron ion binding, zinc ion binding, histone H3K9 demethylase activity, histone H3K4me3 reader activity.

**Biological process:** protein demethylation, transcription initiation-coupled chromatin remodeling, negative regulation of rDNA heterochromatin formation.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2017-09-20.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2017-09-20 |

**Reported phenotype names (ClinVar):** not provided, RECLASSIFIED - ADRA2C POLYMORPHISM, RECLASSIFIED - ADRB1 POLYMORPHISM, none provided.

## Similar variants {#similar}

Related PHF2 variant pages (same residue, condition, or type): [PHF2 c.299+7T>A](/variant/phf2-c-299-plus-7t-a), [PHF2 c.789+10G>A](/variant/phf2-c-789-plus-10g-a), [PHF2 p.Asp103=](/variant/phf2-p-asp103), [PHF2 p.Leu645=](/variant/phf2-p-leu645), [PHF2 p.Pro786=](/variant/phf2-p-pro786), [PHF2 p.Pro988=](/variant/phf2-p-pro988), [PHF2 p.Ser725=](/variant/phf2-p-ser725), [PHF2 p.Ser738=](/variant/phf2-p-ser738).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 778436). 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.*