# NM_001394783.1(CCR5):c.894del (p.Phe299fs)

https://sugi.bio/variant/ccr5-p-phe299fs

## Summary

**CCR5 p.Phe299fs (c.894del)** is classified **Benign** in CCR5 (ClinVar, No assertion criteria, 1 submitter; last evaluated 1997-07-01). Rare (popmax 0.94%, eas); Associated with CCR5 POLYMORPHISM, ORIENTAL 1.

**At a glance:** Benign · review: No assertion criteria · rsID rs796065305 · 1 submitter · 1 linked condition · rare (popmax 0.94%, eas)

## For patients & families {#patients}

This is a change in the CCR5 gene that is classified as benign — not considered disease-causing, submitted by 1 submitter, and is linked to CCR5 POLYMORPHISM, ORIENTAL 1.

*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 | [CCR5](https://sugi.bio/atlas/gene/CCR5/) |
| Protein change (HGVS p.) | p.Phe299fs |
| Coding change (HGVS c.) | c.894del |
| MANE Select transcript | [NM_001394783](https://www.ncbi.nlm.nih.gov/nuccore/NM_001394783) |
| dbSNP | [rs796065305](https://www.ncbi.nlm.nih.gov/snp/rs796065305/) |
| Variant type | Deletion |
| Location | chr3:46373795-46373795 (GRCh38) |
| ClinVar | [VCV8185](https://www.ncbi.nlm.nih.gov/clinvar/variation/8185/) |

**All HGVS expressions:** `NC_000003.11:g.46415287del`, `NC_000003.12:g.46373796del`, `NG_012637.1:g.8655del`, `NM_000579.4:c.894del`, `NM_001100168.2:c.894del`, `NM_001394783.1:c.894del`

## 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 (below), not from a missing predictor score.
- Conservation: phyloP 11.892, GERP 1.85, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.592, pLI 0.18146. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in the last exon (2 of 2)** — predicted to **escape NMD**, so the truncated protein is likely expressed. An input to PVS1, not an applied code.
- CADD: **PHRED 27.5**. 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: **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 (gnomAD v4.1): grpmax **0.94%** (eas) · FAF95 0.866% · FAF99 0.837% · 422/44,884 in the highest group · 435/1,613,942 alleles overall — rare (popmax 0.94%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.94% | 106 |
| Remaining individuals (not grpmax-eligible) | 0.0192% | 5,208 |
| European (non-Finnish) | 8.48e-05% | 1,179,830 |

*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}

**CCR5** population constraint: LOEUF 1.592, pLI 0.18146, missense-Z -0.38831. *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 **299** lies in an α-helix.

AlphaFold model confidence (whole protein): pLDDT 85.41, 66% of residues very-high.

**26 experimental structure(s)** (PDB): [2L87](https://www.rcsb.org/structure/2L87), [2MZX](https://www.rcsb.org/structure/2MZX), [2RLL](https://www.rcsb.org/structure/2RLL), [2RRS](https://www.rcsb.org/structure/2RRS), [4MBS](https://www.rcsb.org/structure/4MBS), [5UIW](https://www.rcsb.org/structure/5UIW).

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

*Describes the biological roles of CCR5 (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:** CCR5's established molecular role includes actin binding. In Reactome, CCR5 is annotated in disease pathway(s) including **Binding and entry of HIV virion**.

**Disease mechanism (Reactome):** CCR5 loss or alteration is curated in [Binding and entry of HIV virion](https://reactome.org/content/detail/R-HSA-173107).

### Pathways affected {#pathways}

CCR5 participates in **5 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Binding and entry of HIV virion](https://reactome.org/content/detail/R-HSA-173107) | curated |
| [Chemokine receptors bind chemokines](https://reactome.org/content/detail/R-HSA-380108) | curated |
| [Differentiation of Circulating Monocytes](https://reactome.org/content/detail/R-HSA-9968734) | curated |
| [G alpha (i) signalling events](https://reactome.org/content/detail/R-HSA-418594) | curated |
| [Interleukin-10 signaling](https://reactome.org/content/detail/R-HSA-6783783) | curated |

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

**Molecular function:** actin binding, C-C chemokine receptor activity, C-C chemokine binding, identical protein binding, chemokine (C-C motif) ligand 5 binding.

**Biological process:** MAPK cascade, calcium ion transport, G protein-coupled receptor signaling pathway, cell-cell signaling, release of sequestered calcium ion into cytosol by sarcoplasmic reticulum, calcium-mediated signaling.

## Clinical significance {#significance}

**Benign** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 1997-07-01.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| OMIM | Benign | no assertion criteria provided | literature only | 1997-07-01 |

## Associated conditions {#conditions}

[CCR5 POLYMORPHISM, ORIENTAL 1](https://sugi.bio/atlas/disease/ccr5-polymorphism-oriental-1/).

**Reported phenotype names (ClinVar):** CCR5 POLYMORPHISM, ORIENTAL 1.

## Similar variants {#similar}

Related CCR5 variant pages (same residue, condition, or type): [CCR5 p.Thr239Ala](/variant/ccr5-p-thr239ala), [CCR5 p.Gly106Arg](/variant/ccr5-p-gly106arg), [CCR5 p.Ile23=](/variant/ccr5-p-ile23), [CCR5 p.Phe247=](/variant/ccr5-p-phe247), [CCR5 p.Thr141=](/variant/ccr5-p-thr141), [CCR5 p.Ser185fs](/variant/ccr5-p-ser185fs).

### 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 8185). 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.*