# NM_172351.3(CD46):c.97G>C (p.Asp33His)

https://sugi.bio/variant/cd46-p-asp33his

## Summary

**CD46 p.Asp33His (c.97G>C)** is classified **Conflicting classifications of pathogenicity** in CD46 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-10-02). AlphaMissense: ambiguous (0.3833); Absent from gnomAD v4.1; Associated with atypical hemolytic-uremic syndrome with MCP/CD46 anomaly.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs2102512645 · 4 submitters · 2 linked conditions · AlphaMissense ambiguous · absent from gnomAD v4.1

## 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 4 submitters, and is linked to atypical hemolytic-uremic syndrome with MCP/CD46 anomaly.

*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:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0018552/index) · [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.Asp33His |
| Coding change (HGVS c.) | c.97G>C |
| MANE Select transcript | [NM_172351](https://www.ncbi.nlm.nih.gov/nuccore/NM_172351) |
| dbSNP | [rs2102512645](https://www.ncbi.nlm.nih.gov/snp/rs2102512645/) |
| Variant type | single nucleotide variant |
| Location | chr1:207752309-207752309 (GRCh38) |
| ClinVar | [VCV1163185](https://www.ncbi.nlm.nih.gov/clinvar/variation/1163185/) |

**All HGVS expressions:** `LRG_155:g.5253G>C`, `LRG_155t1:c.97G>C`, `NC_000001.10:g.207925654G>C`, `NC_000001.11:g.207752309G>C`, `NG_009296.1:g.5253G>C`, `NM_002389.4:c.97G>C`, `NM_153826.4:c.97G>C`, `NM_172350.3:c.97G>C`, `NM_172351.3:c.97G>C`, `NM_172352.3:c.97G>C`, `NM_172353.3:c.97G>C`, `NM_172355.3:c.97G>C`, `NM_172356.3:c.97G>C`, `NM_172357.3:c.97G>C`, `NM_172358.3:c.97G>C`, `NM_172359.3:c.97G>C`, `NM_172361.3:c.97G>C`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense makes no call; REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate — descriptive only.

- AlphaMissense **ambiguous** (0.3833) — no call either way
- REVEL 0.231 (benign-leaning)
- SaProt LLR -6.898 (tolerated)
- → **In-silico consensus:** REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate
- SpliceAI predicts **donor loss** (Δ 0.86) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 9.643, GERP 1.46, phastCons 1 — highly conserved
- CADD: **PHRED 30.0**. 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 0.88** across the covering region of the MANE Select transcript (207,752,213–207,790,301), spanning 38,088 bp. Chi-square p 0.012. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.86**, acceptor gain **0.01**, donor gain **0.00**. Largest is donor loss.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.86**, acceptor gain **0.01**, donor gain **0.00**.
- Pangolin: Δ**0.62** (loss), gain 0.01 / loss 0.62. 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: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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 2025-10-02.

**Submitter consensus:** conflicting (3 Likely pathogenic, 1 Uncertain significance).

**Submission history:** 4 submissions (2020–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Mayo Clinic Laboratories, Mayo Clinic | Likely pathogenic | criteria provided, single submitter | clinical testing | 2020-02-19 |
| Genomenon, Inc, Genomenon, Inc | Uncertain significance | criteria provided, single submitter | curation | 2025-10-02 |
| MVZ Medizinische Genetik Mainz | Likely pathogenic | criteria provided, single submitter | clinical testing | 2025-01-30 |
| Blueprint Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2022-09-26 |

## Associated conditions {#conditions}

[atypical hemolytic-uremic syndrome with MCP/CD46 anomaly](https://sugi.bio/atlas/disease/atypical-hemolytic-uremic-syndrome-with-mcp-cd46-anomaly/), [atypical hemolytic-uremic syndrome](https://sugi.bio/atlas/disease/atypical-hemolytic-uremic-syndrome/).

**Reported phenotype names (ClinVar):** Atypical hemolytic-uremic syndrome with MCP/CD46 anomaly, not provided, Atypical hemolytic-uremic syndrome, CD46-related disorders, HEMOLYTIC UREMIC SYNDROME, ATYPICAL, SUSCEPTIBILITY TO, 2, AHUS, SUSCEPTIBILITY TO, 2, none provided.

## Similar variants {#similar}

Related CD46 variant pages (same residue, condition, or type): [CD46 p.Asp33Tyr](/variant/cd46-p-asp33tyr), [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 2026-10-15); 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 1163185). 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.*