# NM_006610.4(MASP2):c.612G>A (p.Pro204=)

https://sugi.bio/variant/masp2-p-pro204

## Summary

**MASP2 p.Pro204= (c.612G>A)** is classified **Benign** in MASP2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-01-22). Low-frequency (popmax 2.76%, afr); Associated with immunodeficiency due to MASP-2 deficiency.

**At a glance:** Benign · review: Multiple submitters · rsID rs72550853 · 5 submitters · 1 linked condition · low-frequency (popmax 2.76%, afr)

## For patients & families {#patients}

This is a change in the MASP2 gene that is classified as benign — not considered disease-causing, submitted by 5 submitters, and is linked to immunodeficiency due to MASP-2 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 |
| Age of onset (of this condition) | Adolescent |
| Diagnostic panels | MASP2 is a diagnostic-grade gene on 1 Genomics England panel |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0017512/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [MASP2](https://sugi.bio/atlas/gene/MASP2/) |
| Protein change (HGVS p.) | p.Pro204= |
| Coding change (HGVS c.) | c.612G>A |
| MANE Select transcript | [NM_006610](https://www.ncbi.nlm.nih.gov/nuccore/NM_006610) |
| dbSNP | [rs72550853](https://www.ncbi.nlm.nih.gov/snp/rs72550853/) |
| Variant type | single nucleotide variant |
| Location | chr1:11043468-11043468 (GRCh38) |
| ClinVar | [VCV291798](https://www.ncbi.nlm.nih.gov/clinvar/variation/291798/) |

**All HGVS expressions:** `LRG_82:g.8761G>A`, `LRG_82t1:c.612G>A`, `NC_000001.10:g.11103525C>T`, `NC_000001.11:g.11043468C>T`, `NG_007289.2:g.8761G>A`, `NM_006610.4:c.612G>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 (below), not from a missing predictor score.
- Conservation: phyloP -13.925, GERP -3.76 — fast-evolving / accelerated position
- CADD: **PHRED 1.946**. 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: **below the reporting threshold**. This position is scored for a different substitution (C>A, Δ0.31 acceptor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **2.76%** (afr) · FAF95 2.66% · FAF99 2.62% · 2,066/74,962 in the highest group · 2,376/1,610,056 alleles overall — low-frequency (popmax 2.76%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 2.76% | 36 |
| Remaining individuals (not grpmax-eligible) | 0.194% | 516 |
| Admixed American | 0.151% | 660 |
| Middle Eastern | 0.0831% | 1,203 |
| South Asian | 0.0311% | 3,220 |
| European (non-Finnish) | 0.0056% | 17,858 |

*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}

**MASP2** population constraint: LOEUF 1.159, pLI 3.9953e-13, missense-Z -0.20371; ClinGen dosage — haploinsufficiency gene assoc. with recessive phenotype, triplosensitivity Not yet evaluated/3. *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 **204** lies in the cub 2 domain.

AlphaFold model confidence (whole protein): pLDDT 89.73, 74% of residues very-high.

**10 experimental structure(s)** (PDB): [1Q3X](https://www.rcsb.org/structure/1Q3X), [1SZB](https://www.rcsb.org/structure/1SZB), [1ZJK](https://www.rcsb.org/structure/1ZJK), [3TVJ](https://www.rcsb.org/structure/3TVJ), [5JPM](https://www.rcsb.org/structure/5JPM), [7PQN](https://www.rcsb.org/structure/7PQN).

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

*Describes the biological roles of MASP2 (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:** MASP2's established molecular role includes complement component C4b binding. p.Pro204= falls in the cub 2 domain. In Reactome, MASP2 is annotated in disease pathway(s) including **SARS-CoV-2 activates/modulates innate and adaptive immune responses**.

**Disease mechanism (Reactome):** MASP2 loss or alteration is curated in [SARS-CoV-2 activates/modulates innate and adaptive immune responses](https://reactome.org/content/detail/R-HSA-9705671).

### Pathways affected {#pathways}

MASP2 participates in **4 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [SARS-CoV-2 activates/modulates innate and adaptive immune responses](https://reactome.org/content/detail/R-HSA-9705671) | other |
| [Ficolins bind to repetitive carbohydrate structures on the target cell surface](https://reactome.org/content/detail/R-HSA-2855086) | other |
| [Initial triggering of complement](https://reactome.org/content/detail/R-HSA-166663) | other |
| [Lectin pathway of complement activation](https://reactome.org/content/detail/R-HSA-166662) | other |

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

**Molecular function:** complement component C4b binding, serine-type endopeptidase activity, peptidase activity, identical protein binding, calcium-dependent protein binding.

**Biological process:** complement activation, lectin pathway.

## Clinical significance {#significance}

**Benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-01-22.

**Submitter consensus:** unanimous (5/5 Benign).

**Submission history:** 5 submissions (2018–2026); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Illumina Laboratory Services, Illumina | Benign | criteria provided, single submitter | clinical testing | 2018-01-12 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2018-11-09 |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |
| Mayo Clinic Laboratories, Mayo Clinic | Benign | criteria provided, single submitter | clinical testing | 2025-10-08 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Benign | criteria provided, single submitter | clinical testing | 2026-01-22 |

## Associated conditions {#conditions}

[immunodeficiency due to MASP-2 deficiency](https://sugi.bio/atlas/disease/immunodeficiency-due-to-masp-2-deficiency/).

**Reported phenotype names (ClinVar):** Immunodeficiency due to MASP-2 deficiency, not provided, not specified, MASP2 deficiency, LECTIN COMPLEMENT ACTIVATION PATHWAY, DEFECT IN, 2, AllHighlyPenetrant, none provided.

## Similar variants {#similar}

Related MASP2 variant pages (same residue, condition, or type): [MASP2 p.Pro204Leu](/variant/masp2-p-pro204leu), [MASP2 p.Arg376Ter](/variant/masp2-p-arg376ter), [MASP2 p.Ala149Val](/variant/masp2-p-ala149val), [MASP2 p.Arg29His](/variant/masp2-p-arg29his), [MASP2 p.Arg58Cys](/variant/masp2-p-arg58cys), [MASP2 p.Asp75Asn](/variant/masp2-p-asp75asn), [MASP2 p.Cys396Tyr](/variant/masp2-p-cys396tyr), [MASP2 p.Gly34Ser](/variant/masp2-p-gly34ser).

### 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 291798). 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.*