# NM_172351.3(CD46):c.1050G>A (p.Pro350=)

https://sugi.bio/variant/cd46-p-pro350

## Summary

**CD46 p.Pro350= (c.1050G>A)** is classified **Conflicting classifications of pathogenicity** in CD46 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2023-05-19). Very rare (popmax 0.0011%, sas).

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs1210978043 · 2 submitters · very rare (popmax 0.0011%, sas)

## For patients & families {#patients}

This is a change in the CD46 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 2 submitters.

*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 | [CD46](https://sugi.bio/atlas/gene/CD46/) |
| Protein change (HGVS p.) | p.Pro350= |
| Coding change (HGVS c.) | c.1050G>A |
| MANE Select transcript | [NM_172351](https://www.ncbi.nlm.nih.gov/nuccore/NM_172351) |
| dbSNP | [rs1210978043](https://www.ncbi.nlm.nih.gov/snp/rs1210978043/) |
| Variant type | single nucleotide variant |
| Location | chr1:207785650-207785650 (GRCh38) |
| ClinVar | [VCV1337980](https://www.ncbi.nlm.nih.gov/clinvar/variation/1337980/) |

**All HGVS expressions:** `LRG_155:g.38594G>A`, `LRG_155t1:c.1095G>A`, `NC_000001.10:g.207958995G>A`, `NC_000001.11:g.207785650G>A`, `NG_009296.1:g.38594G>A`, `NM_002389.4:c.1095G>A`, `NM_153826.4:c.1050G>A`, `NM_172350.3:c.973+544G>A`, `NM_172351.3:c.1050G>A`, `NM_172352.3:c.1005G>A`, `NM_172353.3:c.1005G>A`, `NM_172355.3:c.1008G>A`, `NM_172356.3:c.1008G>A`, `NM_172357.3:c.963G>A`, `NM_172358.3:c.1019-6G>A`, `NM_172359.3:c.1095G>A`, `NM_172361.3:c.963G>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 **acceptor loss** (Δ 0.23) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP -1.053, GERP -0.127 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 4.514**. 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 **0.23**, donor loss **0.04**, acceptor gain **0.09**, donor gain **0.00**. Largest is acceptor loss, 31 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.09**, donor gain **0.00**.
  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.*
- Pangolin: Δ**0.21** (loss), gain 0.06 / loss 0.21. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.0011%** (sas) · FAF95 0.00043% · FAF99 0.000313% · 1/90,994 in the highest group · 15/1,610,372 alleles overall — very rare (popmax 0.0011%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.00641% | 15,593 |
| South Asian (grpmax) | 0.0011% | 90,994 |
| European (non-Finnish) | 0.00085% | 117,703 |

Remaining individuals 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}

**CD46** population constraint: LOEUF 0.763, pLI 0.041886, missense-Z 0.75927. *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):

- **atypical hemolytic-uremic syndrome** — Definitive (SD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 82.38, 66% of residues very-high.

**7 experimental structure(s)** (PDB): [1CKL](https://www.rcsb.org/structure/1CKL), [2O39](https://www.rcsb.org/structure/2O39), [3INB](https://www.rcsb.org/structure/3INB), [3L89](https://www.rcsb.org/structure/3L89), [3O8E](https://www.rcsb.org/structure/3O8E), [5FO8](https://www.rcsb.org/structure/5FO8).

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

*Describes the biological roles of CD46 (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:** CD46's established molecular role includes cadherin binding.


### Pathways affected {#pathways}

CD46 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Regulation of Complement cascade](https://reactome.org/content/detail/R-HSA-977606) | curated |

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

**Molecular function:** cadherin binding.

**Biological process:** T cell mediated immunity, regulation of Notch signaling pathway, positive regulation of gene expression, negative regulation of gene expression, positive regulation of interleukin-10 production, obsolete sequestering of extracellular ligand from receptor.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2023-05-19.

**Submitter consensus:** conflicting (1 Likely benign, 1 Uncertain significance).

**Submission history:** 2 submissions (2021–2023); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Genetic Services Laboratory, University of Chicago | Likely benign | criteria provided, single submitter | clinical testing | 2021-06-18 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-05-19 |

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

## Similar variants {#similar}

Related CD46 variant pages (same residue, condition, or type): [CD46 p.Pro350Leu](/variant/cd46-p-pro350leu), [CD46 c.1082+2T>A](/variant/cd46-c-1082-plus-2t-a), [CD46 c.286+1G>C](/variant/cd46-c-286-plus-1g-c), [CD46 c.286+2T>G](/variant/cd46-c-286-plus-2t-g), [CD46 c.287-2A>G](/variant/cd46-c-287-minus-2a-g), [CD46 p.Arg229Ter](/variant/cd46-p-arg229ter), [CD46 p.Arg59Ter](/variant/cd46-p-arg59ter), [CD46 p.Phe242Cys](/variant/cd46-p-phe242cys).

### 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 1337980). 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.*