# NM_006610.4(MASP2):c.408C>T (p.Ala136=)

https://sugi.bio/variant/masp2-p-ala136

## Summary

**MASP2 p.Ala136= (c.408C>T)** is classified **Benign** in MASP2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-22). Low-frequency (popmax 2.6%, afr); Associated with immunodeficiency due to MASP-2 deficiency.

**At a glance:** Benign · review: Multiple submitters · rsID rs138386377 · 3 submitters · 1 linked condition · low-frequency (popmax 2.6%, afr)

## For patients & families {#patients}

This is a change in the MASP2 gene that is classified as benign — not considered disease-causing, submitted by 3 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.Ala136= |
| Coding change (HGVS c.) | c.408C>T |
| MANE Select transcript | [NM_006610](https://www.ncbi.nlm.nih.gov/nuccore/NM_006610) |
| dbSNP | [rs138386377](https://www.ncbi.nlm.nih.gov/snp/rs138386377/) |
| Variant type | single nucleotide variant |
| Location | chr1:11046560-11046560 (GRCh38) |
| ClinVar | [VCV874901](https://www.ncbi.nlm.nih.gov/clinvar/variation/874901/) |

**All HGVS expressions:** `LRG_82:g.5669C>T`, `LRG_82t1:c.408C>T`, `LRG_82t2:c.408C>T`, `NC_000001.10:g.11106617G>A`, `NC_000001.11:g.11046560G>A`, `NG_007289.2:g.5669C>T`, `NM_006610.4:c.408C>T`, `NM_139208.3:c.408C>T`

## 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 -13.227, GERP -3.76 — fast-evolving / accelerated position
- CADD: **PHRED 0.219**. 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 **2.6%** (afr) · FAF95 2.51% · FAF99 2.47% · 1,955/75,064 in the highest group · 2,377/1,613,848 alleles overall — low-frequency (popmax 2.6%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 2.6% | 38 |
| Admixed American | 0.29% | 345 |
| Remaining individuals (not grpmax-eligible) | 0.21% | 477 |
| Middle Eastern | 0.0495% | 2,021 |
| South Asian | 0.0176% | 5,691 |
| Finnish (not grpmax-eligible) | 0.0141% | 7,081 |
| European (non-Finnish) | 0.00746% | 13,409 |
| East Asian | 0.00223% | 44,890 |

*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 30, triplosensitivity Not yet evaluated (0–3 scale). *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 **136** lies in the cub 1 domain; a β-strand.

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.Ala136= falls in the cub 1 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 (3/3 Benign).

**Submission history:** 3 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 | 2018-01-13 |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |
| 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, none provided, AllHighlyPenetrant, MASP2 deficiency, LECTIN COMPLEMENT ACTIVATION PATHWAY, DEFECT IN, 2.

## Similar variants {#similar}

Related MASP2 variant pages (same residue, condition, or type): [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), [MASP2 p.Gly635Arg](/variant/masp2-p-gly635arg).

### 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 2026-07-14); 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 874901). 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.*