# NM_020311.3(ACKR3):c.457C>T (p.Pro153Ser)

https://sugi.bio/variant/ackr3-p-pro153ser

## Summary

**ACKR3 p.Pro153Ser (c.457C>T)** is classified **Likely benign** in ACKR3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-02). AlphaMissense: likely benign (0.0753); Ultra-rare (popmax 0.0567%, amr).

**At a glance:** Likely benign · review: Single submitter · 1 submitter · AlphaMissense likely benign · ultra-rare (popmax 0.0567%, amr)

## For patients & families {#patients}

This is a change in the ACKR3 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 | [ACKR3](https://sugi.bio/atlas/gene/ACKR3/) |
| Protein change (HGVS p.) | p.Pro153Ser |
| Coding change (HGVS c.) | c.457C>T |
| MANE Select transcript | [NM_020311](https://www.ncbi.nlm.nih.gov/nuccore/NM_020311) |
| Variant type | single nucleotide variant |
| Location | chr2:236580922-236580922 (GRCh38) |
| ClinVar | [VCV3998563](https://www.ncbi.nlm.nih.gov/clinvar/variation/3998563/) |

**All HGVS expressions:** `NC_000002.11:g.237489565C>T`, `NC_000002.12:g.236580922C>T`, `NM_020311.3:c.457C>T`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely benign** (0.0753)
- REVEL 0.053 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -5.695 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 0.144, GERP -3.8, phastCons 0.011 — weakly conserved position
- CADD: **PHRED 2.575**. 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 0.83** across the covering region of the MANE Select transcript (236,580,466–236,581,551), spanning 1,085 bp. Chi-square p 0.00028. 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 (gnomAD v4.1): grpmax **0.0567%** (amr) · FAF95 0.0416% · FAF99 0.0365% · 34/60,002 in the highest group · 42/1,614,080 alleles overall — ultra-rare (popmax 0.0567%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.0567% | 1,765 |
| Remaining individuals (not grpmax-eligible) | 0.0064% | 15,623 |
| European (non-Finnish) | 0.000339% | 295,011 |

*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}

**ACKR3** population constraint: LOEUF 0.492, pLI 0.98139, missense-Z 1.6942. *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 **153** lies in a disulfide bond.

AlphaFold model confidence (whole protein): pLDDT 82.47, 41% of residues very-high.

**14 experimental structure(s)** (PDB): [6K3F](https://www.rcsb.org/structure/6K3F), [7SK3](https://www.rcsb.org/structure/7SK3), [7SK4](https://www.rcsb.org/structure/7SK4), [7SK5](https://www.rcsb.org/structure/7SK5), [7SK6](https://www.rcsb.org/structure/7SK6), [7SK7](https://www.rcsb.org/structure/7SK7) — incl. mutant structure 7SK4.

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

*Describes the biological roles of ACKR3 (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:** ACKR3's established molecular role includes scavenger receptor activity.


### Pathways affected {#pathways}

ACKR3 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Chemokine receptors bind chemokines](https://reactome.org/content/detail/R-HSA-380108) | curated |
| [G alpha (i) signalling events](https://reactome.org/content/detail/R-HSA-418594) | curated |

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

**Molecular function:** scavenger receptor activity, C-X-C chemokine receptor activity, C-X-C chemokine binding.

**Biological process:** oculomotor nerve development, receptor internalization, chemokine-mediated signaling pathway, positive regulation of ERK1 and ERK2 cascade, negative regulation of intrinsic apoptotic signaling pathway in response to DNA damage.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-04-02.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2025-04-02 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related ACKR3 variant pages (same residue, condition, or type): [ACKR3 p.Ile210=](/variant/ackr3-p-ile210), [ACKR3 p.Pro201=](/variant/ackr3-p-pro201), [ACKR3 p.Val230Ile](/variant/ackr3-p-val230ile), [ACKR3 p.Ala229Gly](/variant/ackr3-p-ala229gly), [ACKR3 p.Ala241Val](/variant/ackr3-p-ala241val), [ACKR3 p.Ala296Thr](/variant/ackr3-p-ala296thr), [ACKR3 p.Arg162Cys](/variant/ackr3-p-arg162cys), [ACKR3 p.Arg288Trp](/variant/ackr3-p-arg288trp).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); 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 2026-07-14); 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 3998563). 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.*