# NM_017934.7(PHIP):c.2670_2671del (p.Lys891fs)

https://sugi.bio/variant/phip-p-lys891fs

## Summary

**PHIP p.Lys891fs (c.2670_2671del)** is classified **Pathogenic** in PHIP (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-12). No gnomAD frequency available for this variant; Associated with PHIP-related disorder.

**At a glance:** Pathogenic · review: Single submitter · rsID rs2481963256 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the PHIP gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to PHIP-related disorder.

*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 | [PHIP](https://sugi.bio/atlas/gene/PHIP/) |
| Protein change (HGVS p.) | p.Lys891fs |
| Coding change (HGVS c.) | c.2670_2671del |
| MANE Select transcript | [NM_017934](https://www.ncbi.nlm.nih.gov/nuccore/NM_017934) |
| dbSNP | [rs2481963256](https://www.ncbi.nlm.nih.gov/snp/rs2481963256/) |
| Variant type | Deletion |
| Location | chr6:78982984-78982985 (GRCh38) |
| ClinVar | [VCV2630755](https://www.ncbi.nlm.nih.gov/clinvar/variation/2630755/) |

**All HGVS expressions:** `NC_000006.11:g.79692702_79692703del`, `NC_000006.12:g.78982985_78982986del`, `NG_051932.1:g.100314_100315del`, `NM_017934.7:c.2670_2671del`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **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 (below), not from a missing predictor score.
- Conservation: phyloP 7.873, GERP -2.05, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. ClinGen curates **sufficient evidence for haploinsufficiency** in this gene (constraint LOEUF 0.246, pLI 1), supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 23 of 40**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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}

**PHIP** population constraint: LOEUF 0.246, pLI 1, missense-Z 4.4459; 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):

- **PHIP-related behavioral problems-intellectual disability-obesity-dysmorphic features syndrome** — Definitive (AD)

## Protein context {#protein}

Residue **891** lies in the 'disordered' region; a UniProt-annotated variant site (in chujans).

AlphaFold model confidence (whole protein): pLDDT 66.57, 32% of residues very-high.

**146 experimental structure(s)** (PDB): [3MB3](https://www.rcsb.org/structure/3MB3), [5ENB](https://www.rcsb.org/structure/5ENB), [5ENC](https://www.rcsb.org/structure/5ENC), [5ENE](https://www.rcsb.org/structure/5ENE), [5ENF](https://www.rcsb.org/structure/5ENF), [5ENH](https://www.rcsb.org/structure/5ENH).

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

*Describes the biological roles of PHIP (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:** PHIP's established molecular role includes histone reader activity. p.Lys891fs falls in the disordered region.


### Pathways affected {#pathways}

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

| Pathway (Reactome) | Evidence |
| --- | --- |
| [RHOBTB2 GTPase cycle](https://reactome.org/content/detail/R-HSA-9013418) | curated |

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

**Molecular function:** histone reader activity.

**Biological process:** positive regulation of transcription by RNA polymerase II, negative regulation of extrinsic apoptotic signaling pathway.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-09-12.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Pathogenic | criteria provided, single submitter | clinical testing | 2023-09-12 |

## Associated conditions {#conditions}

[PHIP-related disorder](https://sugi.bio/atlas/disease/phip-related-disorder/).

**Reported phenotype names (ClinVar):** PHIP-related disorder, PHIP-related condition, PHIP-related disorders.

## Similar variants {#similar}

Related PHIP variant pages (same residue, condition, or type): [PHIP p.Ile307fs](/variant/phip-p-ile307fs), [PHIP p.Glu904fs](/variant/phip-p-glu904fs), [PHIP p.Tyr348fs](/variant/phip-p-tyr348fs), [PHIP p.Val771Ile](/variant/phip-p-val771ile), [PHIP c.1096-2A>C](/variant/phip-c-1096-minus-2a-c), [PHIP c.822+1G>A](/variant/phip-c-822-plus-1g-a), [PHIP p.Glu55Ter](/variant/phip-p-glu55ter), [PHIP p.Glu755Ter](/variant/phip-p-glu755ter).

### 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 2630755). 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.*