# NM_052813.5(CARD9):c.126C>T (p.Pro42=)

https://sugi.bio/variant/card9-p-pro42

## Summary

**CARD9 p.Pro42= (c.126C>T)** is classified **Benign/Likely benign** in CARD9 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-02-04). Common (popmax 52%, amr) — too common for a highly-penetrant pathogenic allele; Associated with predisposition to invasive fungal disease due to CARD9 deficiency.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs10781499 · 8 submitters · 1 linked condition · common (popmax 52%, amr) — too common for a highly-penetrant pathogenic allele

## For patients & families {#patients}

This is a change in the CARD9 gene that is classified as benign/likely benign — not considered disease-causing, submitted by 8 submitters, and is linked to predisposition to invasive fungal disease due to CARD9 deficiency.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Diagnostic panels | CARD9 is a diagnostic-grade gene on 3 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0017795/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CARD9](https://sugi.bio/atlas/gene/CARD9/) |
| Protein change (HGVS p.) | p.Pro42= |
| Coding change (HGVS c.) | c.126C>T |
| MANE Select transcript | [NM_052813](https://www.ncbi.nlm.nih.gov/nuccore/NM_052813) |
| dbSNP | [rs10781499](https://www.ncbi.nlm.nih.gov/snp/rs10781499/) |
| Variant type | single nucleotide variant |
| Location | chr9:136371953-136371953 (GRCh38) |
| ClinVar | [VCV365857](https://www.ncbi.nlm.nih.gov/clinvar/variation/365857/) |

**All HGVS expressions:** `LRG_178:g.6729C>T`, `LRG_178t1:c.126C>T`, `NC_000009.11:g.139266405G>A`, `NC_000009.12:g.136371953G>A`, `NG_021197.1:g.6729C>T`, `NM_052813.5:c.126C>T`, `NM_052814.4:c.126C>T`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — common (popmax 52%, amr) — too common for a highly-penetrant pathogenic allele.

- **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 (below), not from a missing predictor score.
- Conservation: phyloP -7.754, GERP -3.41 — fast-evolving / accelerated position
- CADD: **PHRED 7.225**. 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: **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 **52%** (amr) · FAF95 51.5% · FAF99 51.3% · 31,168/59,940 in the highest group · 665,668/1,609,980 alleles overall — common (popmax 52%, amr) — too common for a highly-penetrant pathogenic allele.

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 52% | 2 |
| European (non-Finnish) | 43% | 2 |
| Finnish (not grpmax-eligible) | 41.6% | 2 |
| Amish (not grpmax-eligible) | 41.4% | 2 |
| Remaining individuals (not grpmax-eligible) | 39.5% | 3 |
| Ashkenazi Jewish (not grpmax-eligible) | 35.5% | 3 |
| South Asian | 32.1% | 3 |
| East Asian | 31.7% | 3 |
| African / African-American | 28.3% | 4 |
| Middle Eastern | 23.9% | 4 |

*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}

**CARD9** population constraint: LOEUF 1.143, pLI 6.2657e-17, missense-Z -0.92366. *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 **42** lies in the card domain; a UniProt-annotated variant site (in imd103; reduced cytokine production in response to c.albicans infection; impaired nf-kappa-b transcriptional activity); an α-helix.

AlphaFold model confidence (whole protein): pLDDT 81.24, 61% of residues very-high.

**8 experimental structure(s)** (PDB): [6E25](https://www.rcsb.org/structure/6E25), [6E26](https://www.rcsb.org/structure/6E26), [6E27](https://www.rcsb.org/structure/6E27), [6E28](https://www.rcsb.org/structure/6E28), [6N2M](https://www.rcsb.org/structure/6N2M), [6N2P](https://www.rcsb.org/structure/6N2P).

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

*Describes the biological roles of CARD9 (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:** CARD9's established molecular role includes signaling adaptor activity. p.Pro42= falls in the card domain.


### Pathways affected {#pathways}

CARD9 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [CLEC7A (Dectin-1) signaling](https://reactome.org/content/detail/R-HSA-5607764) | curated |
| [NOD1/2 Signaling Pathway](https://reactome.org/content/detail/R-HSA-168638) | electronic |

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

**Molecular function:** signaling adaptor activity, identical protein binding, protein homodimerization activity, CARD domain binding.

**Biological process:** positive regulation of cytokine production, neutrophil mediated immunity, immunoglobulin mediated immune response, positive regulation of granulocyte macrophage colony-stimulating factor production, positive regulation of interleukin-17 production, positive regulation of interleukin-6 production.

## Clinical significance {#significance}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-02-04.

**Submitter consensus:** conflicting (7 Benign, 1 Likely benign).

**Submission history:** 8 submissions (2016–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Benign | criteria provided, single submitter | clinical testing | 2016-03-29 |
| Illumina Laboratory Services, Illumina | Benign | criteria provided, single submitter | clinical testing | 2018-01-12 |
| Genome-Nilou Lab | Benign | criteria provided, single submitter | clinical testing | 2021-07-14 |
| Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan | Benign | criteria provided, single submitter | clinical testing | 2024-01-24 |
| Mayo Clinic Laboratories, Mayo Clinic | Benign | criteria provided, single submitter | clinical testing | 2022-09-06 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-02-04 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-27 |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |

## Associated conditions {#conditions}

[predisposition to invasive fungal disease due to CARD9 deficiency](https://sugi.bio/atlas/disease/predisposition-to-invasive-fungal-disease-due-to-card9-deficiency/).

**Reported phenotype names (ClinVar):** Predisposition to invasive fungal disease due to CARD9 deficiency, not specified, not provided, AllHighlyPenetrant, CARD9 IMMUNODEFICIENCY, IMMUNODEFICIENCY 103, SUSCEPTIBILITY TO FUNGAL INFECTIONS, Candidiasis, familial, 2, autosomal recessive, none provided.

## Similar variants {#similar}

Related CARD9 variant pages (same residue, condition, or type): [CARD9 p.Pro42Leu](/variant/card9-p-pro42leu), [CARD9 p.Gln289Ter](/variant/card9-p-gln289ter), [CARD9 p.Gln295Ter](/variant/card9-p-gln295ter), [CARD9 c.-126C>A](/variant/card9-c-minus-126c-a), [CARD9 p.Ala109Val](/variant/card9-p-ala109val), [CARD9 p.Ala190Val](/variant/card9-p-ala190val), [CARD9 p.Ala198Thr](/variant/card9-p-ala198thr), [CARD9 p.Ala199Val](/variant/card9-p-ala199val).

### 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 365857). 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.*