# NM_203416.4(CD163):c.45T>A (p.Ala15=)

https://sugi.bio/variant/cd163-p-ala15

## Summary

**CD163 p.Ala15= (c.45T>A)** is classified **Uncertain significance** in CD163 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-06). Very rare (popmax 0.000515%, nfe); Associated with lung adenocarcinoma.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs1470715220 · 1 submitter · 1 linked condition · very rare (popmax 0.000515%, nfe)

## For patients & families {#patients}

This is a change in the CD163 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to lung adenocarcinoma.

*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.*

|  |  |
| --- | --- |
| Clinical trials | 220 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CD163](https://sugi.bio/atlas/gene/CD163/) |
| Protein change (HGVS p.) | p.Ala15= |
| Coding change (HGVS c.) | c.45T>A |
| MANE Select transcript | [NM_203416](https://www.ncbi.nlm.nih.gov/nuccore/NM_203416) |
| dbSNP | [rs1470715220](https://www.ncbi.nlm.nih.gov/snp/rs1470715220/) |
| Variant type | single nucleotide variant |
| Location | chr12:7503646-7503646 (GRCh38) |
| ClinVar | [VCV2431073](https://www.ncbi.nlm.nih.gov/clinvar/variation/2431073/) |

**All HGVS expressions:** `NC_000012.11:g.7656242A>T`, `NC_000012.12:g.7503646A>T`, `NG_029826.1:g.5173T>A`, `NM_001370145.1:c.45T>A`, `NM_001370146.1:c.45T>A`, `NM_004244.6:c.45T>A`, `NM_203416.4:c.45T>A`, `NR_163255.1:n.132T>A`

## 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 **donor loss** (Δ 0.25) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP -0.01, GERP -2.66, phastCons 0.012 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 7.947**. 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 **0.00**, donor loss **0.25**, acceptor gain **0.00**, donor gain **0.02**. Largest is donor loss, 42 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.02**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Population frequency (gnomAD v4.1): grpmax **0.000515%** (nfe) · FAF95 0.000185% · FAF99 0.000122% · 6/1,165,246 in the highest group · 6/1,441,832 alleles overall — very rare (popmax 0.000515%, nfe).

*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}

**CD163** population constraint: LOEUF 0.56, pLI 0.00053022, missense-Z 3.7869. *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 77.72, 29% of residues very-high.

**14 experimental structure(s)** (PDB): [8XMK](https://www.rcsb.org/structure/8XMK), [8XMP](https://www.rcsb.org/structure/8XMP), [8XMQ](https://www.rcsb.org/structure/8XMQ), [8XMW](https://www.rcsb.org/structure/8XMW), [9FHB](https://www.rcsb.org/structure/9FHB), [9FMU](https://www.rcsb.org/structure/9FMU).

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

*Describes the biological roles of CD163 (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:** CD163's established molecular role includes scaffold protein binding. In Reactome, CD163 is annotated in disease pathway(s) including **CD163 mediating an anti-inflammatory response**.

**Disease mechanism (Reactome):** CD163 loss or alteration is curated in [CD163 mediating an anti-inflammatory response](https://reactome.org/content/detail/R-HSA-9662834).

### Pathways affected {#pathways}

CD163 participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [CD163 mediating an anti-inflammatory response](https://reactome.org/content/detail/R-HSA-9662834) | other |
| [Differentiation of Circulating Monocytes](https://reactome.org/content/detail/R-HSA-9968734) | curated |
| [Scavenging of heme from plasma](https://reactome.org/content/detail/R-HSA-2168880) | other |

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

**Molecular function:** scaffold protein binding.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-06-06.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Liquid Biopsy and Cancer Interception Group, Pfizer-University of Granada-Junta de Andalucía Centre for Genomics and Oncological Research | Uncertain significance | criteria provided, single submitter | research | 2022-06-06 |

## Associated conditions {#conditions}

[lung adenocarcinoma](https://sugi.bio/atlas/disease/lung-adenocarcinoma/).

**Reported phenotype names (ClinVar):** Lung adenocarcinoma, Adenocarcinoma of lung, somatic, Adenocarcinoma of lung.

## Similar variants {#similar}

Related CD163 variant pages (same residue, condition, or type): [CD163 c.3344-144C>G](/variant/cd163-c-3344-minus-144c-g), [CD163 c.3344-24C>A](/variant/cd163-c-3344-minus-24c-a), [CD163 c.3344-56G>A](/variant/cd163-c-3344-minus-56g-a), [CD163 c.457+9T>A](/variant/cd163-c-457-plus-9t-a), [CD163 p.Asn642Lys](/variant/cd163-p-asn642lys), [CD163 p.Asn892=](/variant/cd163-p-asn892), [CD163 p.Cys1008=](/variant/cd163-p-cys1008), [CD163 p.Ile342Val](/variant/cd163-p-ile342val).

### 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 2431073). 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.*