# NM_014143.4(CD274):c.437C>G (p.Pro146Arg)

https://sugi.bio/variant/cd274-p-pro146arg

## Summary

**CD274 p.Pro146Arg (c.437C>G)** is classified **Likely benign** in CD274 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-01). AlphaMissense: likely benign (0.1271); Rare (popmax 0.503%, amr).

**At a glance:** Likely benign · review: Single submitter · rsID rs17718883 · 1 submitter · AlphaMissense likely benign · rare (popmax 0.503%, amr)

## For patients & families {#patients}

This is a change in the CD274 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 | [CD274](https://sugi.bio/atlas/gene/CD274/) |
| Protein change (HGVS p.) | p.Pro146Arg |
| Coding change (HGVS c.) | c.437C>G |
| MANE Select transcript | [NM_014143](https://www.ncbi.nlm.nih.gov/nuccore/NM_014143) |
| dbSNP | [rs17718883](https://www.ncbi.nlm.nih.gov/snp/rs17718883/) |
| Variant type | single nucleotide variant |
| Location | chr9:5462876-5462876 (GRCh38) |
| ClinVar | [VCV2659049](https://www.ncbi.nlm.nih.gov/clinvar/variation/2659049/) |

**All HGVS expressions:** `NC_000009.11:g.5462876C>G`, `NC_000009.12:g.5462876C>G`, `NM_001267706.2:c.95C>G`, `NM_001314029.2:c.437C>G`, `NM_014143.4:c.437C>G`, `NR_052005.2:n.506C>G`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.1271)
- REVEL 0.121 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -7.367 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 3.456, GERP 0.083, phastCons 0.998 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 19.99**. 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 1.02** across the covering region of the MANE Select transcript (5,456,114–5,467,859), spanning 11,745 bp. Chi-square p 0.73. 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 **0.503%** (amr) · FAF95 0.457% · FAF99 0.438% · 302/59,990 in the highest group · 6,557/1,613,860 alleles overall — rare (popmax 0.503%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Amish (not grpmax-eligible) | 2.41% | 41 |
| Ashkenazi Jewish (not grpmax-eligible) | 1.64% | 61 |
| Admixed American (grpmax) | 0.503% | 199 |
| Remaining individuals (not grpmax-eligible) | 0.45% | 222 |
| European (non-Finnish) | 0.446% | 224 |
| Finnish (not grpmax-eligible) | 0.206% | 485 |
| Middle Eastern | 0.0826% | 1,211 |
| African / African-American | 0.06% | 1,667 |
| South Asian | 0.0209% | 4,793 |

Amish 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}

**CD274** population constraint: LOEUF 0.476, pLI 0.98208, missense-Z 0.44887. *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 **146** lies in a turn; the ig-like c2-type domain.

AlphaFold model confidence (whole protein): pLDDT 88.13, 70% of residues very-high.

**78 experimental structure(s)** (PDB): [3BIK](https://www.rcsb.org/structure/3BIK), [3BIS](https://www.rcsb.org/structure/3BIS), [3FN3](https://www.rcsb.org/structure/3FN3), [3SBW](https://www.rcsb.org/structure/3SBW), [4Z18](https://www.rcsb.org/structure/4Z18), [4ZQK](https://www.rcsb.org/structure/4ZQK) — incl. mutant structure 3SBW.

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

*Describes the biological roles of CD274 (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:** CD274's established molecular role includes transcription coactivator activity. p.Pro146Arg falls in the ig-like c2-type domain.


### Pathways affected {#pathways}

CD274 participates in **7 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [AMPK-induced ERAD and lysosome mediated degradation of PD-L1(CD274)](https://reactome.org/content/detail/R-HSA-9931269) | curated |
| [Co-inhibition by PD-1](https://reactome.org/content/detail/R-HSA-389948) | curated |
| [GSK3B-mediated proteasomal degradation of PD-L1(CD274)](https://reactome.org/content/detail/R-HSA-9929356) | curated |
| [PD-L1(CD274) glycosylation and translocation to plasma membrane](https://reactome.org/content/detail/R-HSA-9931295) | curated |
| [Regulation of PD-L1(CD274) translation](https://reactome.org/content/detail/R-HSA-9909620) | curated |
| [SPOP-mediated proteasomal degradation of PD-L1(CD274)](https://reactome.org/content/detail/R-HSA-9929491) | curated |
| [STAT3 nuclear events downstream of ALK signaling](https://reactome.org/content/detail/R-HSA-9701898) | curated |

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

**Molecular function:** transcription coactivator activity, receptor ligand activity.

**Biological process:** negative regulation of T cell mediated immune response to tumor cell, immune response, signal transduction, cell surface receptor signaling pathway, T cell costimulation, negative regulation of type II interferon production.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-07-01.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2022-07-01 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related CD274 variant pages (same residue, condition, or type): [CD274 p.Pro146Thr](/variant/cd274-p-pro146thr), [CD274 c.*2635A>G](/variant/cd274-c-star-2635a-g), [CD274 c.*93G>A](/variant/cd274-c-star-93g-a), [CD274 p.Arg186Ser](/variant/cd274-p-arg186ser), [CD274 p.Asn183Thr](/variant/cd274-p-asn183thr), [CD274 p.Asn278His](/variant/cd274-p-asn278his), [CD274 p.Glu205Asp](/variant/cd274-p-glu205asp), [CD274 p.Glu217Lys](/variant/cd274-p-glu217lys).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 2026-10-14); 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 2659049). 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.*