# NM_198576.4(AGRN):c.1188G>A (p.Pro396=)

https://sugi.bio/variant/agrn-p-pro396

## Summary

**AGRN p.Pro396= (c.1188G>A)** is classified **Likely benign** in AGRN (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-01-13). Ultra-rare (popmax 0.0846%, mid); Associated with congenital myasthenic syndrome 8.

**At a glance:** Likely benign · review: Multiple submitters · rsID rs138841641 · 5 submitters · 1 linked condition · ultra-rare (popmax 0.0846%, mid)

## For patients & families {#patients}

This is a change in the AGRN gene that is classified as likely benign — not considered disease-causing, submitted by 5 submitters, and is linked to congenital myasthenic syndrome 8.

*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/0015908/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [AGRN](https://sugi.bio/atlas/gene/AGRN/) |
| Protein change (HGVS p.) | p.Pro396= |
| Coding change (HGVS c.) | c.1188G>A |
| MANE Select transcript | [NM_198576](https://www.ncbi.nlm.nih.gov/nuccore/NM_198576) |
| dbSNP | [rs138841641](https://www.ncbi.nlm.nih.gov/snp/rs138841641/) |
| Variant type | single nucleotide variant |
| Location | chr1:1041966-1041966 (GRCh38) |
| ClinVar | [VCV541206](https://www.ncbi.nlm.nih.gov/clinvar/variation/541206/) |

**All HGVS expressions:** `LRG_198:g.26844G>A`, `NC_000001.10:g.977346G>A`, `NC_000001.11:g.1041966G>A`, `NG_016346.1:g.26844G>A`, `NM_001305275.2:c.1188G>A`, `NM_001364727.2:c.873G>A`, `NM_198576.4:c.1188G>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 -5.455, GERP -2.68 — fast-evolving / accelerated position
- CADD: **PHRED 0.984**. 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 **0.0846%** (mid) · FAF95 0.0333% · FAF99 0.0216% · 5/5,912 in the highest group · 1,312/1,611,798 alleles overall — ultra-rare (popmax 0.0846%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Ashkenazi Jewish (not grpmax-eligible) | 3% | 33 |
| Remaining individuals (not grpmax-eligible) | 0.229% | 437 |
| Middle Eastern (grpmax) | 0.0846% | 1,182 |
| African / African-American | 0.024% | 4,167 |
| European (non-Finnish) | 0.0203% | 4,915 |
| Admixed American | 0.0133% | 7,501 |
| Finnish (not grpmax-eligible) | 0.00961% | 10,401 |
| South Asian | 0.00439% | 22,766 |

Ashkenazi Jewish 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}

**AGRN** population constraint: LOEUF 0.73, pLI 1.5815e-20, missense-Z -2.5712; ClinGen dosage — haploinsufficiency 30, triplosensitivity 0 (0–3 scale). *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):

- **congenital myasthenic syndrome 8** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 69.79, 12% of residues very-high.

**1 experimental structure(s)** (PDB): [8S9P](https://www.rcsb.org/structure/8S9P).

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

*Describes the biological roles of AGRN (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:** AGRN's established molecular role includes receptor ligand activity. In Reactome, AGRN is annotated in disease pathway(s) including **Defective B3GALT6 causes EDSP2 and SEMDJL1**, **Defective B3GAT3 causes JDSSDHD**.

**Disease mechanism (Reactome):** AGRN loss or alteration is curated in [Defective B3GALT6 causes EDSP2 and SEMDJL1](https://reactome.org/content/detail/R-HSA-4420332), [Defective B3GAT3 causes JDSSDHD](https://reactome.org/content/detail/R-HSA-3560801), [Defective B4GALT7 causes EDS, progeroid type](https://reactome.org/content/detail/R-HSA-3560783).

### Pathways affected {#pathways}

AGRN participates in **21 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective B3GALT6 causes EDSP2 and SEMDJL1](https://reactome.org/content/detail/R-HSA-4420332) | curated |
| ⚕ [Defective B3GAT3 causes JDSSDHD](https://reactome.org/content/detail/R-HSA-3560801) | curated |
| ⚕ [Defective B4GALT7 causes EDS, progeroid type](https://reactome.org/content/detail/R-HSA-3560783) | curated |
| ⚕ [Defective EXT1 causes exostoses 1, TRPS2 and CHDS](https://reactome.org/content/detail/R-HSA-3656253) | curated |
| ⚕ [Defective EXT2 causes exostoses 2](https://reactome.org/content/detail/R-HSA-3656237) | curated |
| ⚕ [Dengue Virus Attachment and Entry](https://reactome.org/content/detail/R-HSA-9918485) | curated |
| ⚕ [Dengue Virus-Host Interactions](https://reactome.org/content/detail/R-HSA-9918481) | curated |
| ⚕ [RSV-host interactions](https://reactome.org/content/detail/R-HSA-9833110) | curated |
| ⚕ [Respiratory syncytial virus (RSV) attachment and entry](https://reactome.org/content/detail/R-HSA-9820960) | curated |
| ⚕ [Attachment and Entry](https://reactome.org/content/detail/R-HSA-9694614) | electronic |
| [Formation of the dystrophin-glycoprotein complex (DGC)](https://reactome.org/content/detail/R-HSA-9913351) | curated |
| [Glycosaminoglycan-protein linkage region biosynthesis](https://reactome.org/content/detail/R-HSA-1971475) | curated |
| [HS-GAG degradation](https://reactome.org/content/detail/R-HSA-2024096) | curated |
| [Initiation of coagulation cascade](https://reactome.org/content/detail/R-HSA-9769735) | curated |
| [Regulation of clotting cascade](https://reactome.org/content/detail/R-HSA-9769739) | curated |
| [Retinoid metabolism and transport](https://reactome.org/content/detail/R-HSA-975634) | curated |
| [ECM proteoglycans](https://reactome.org/content/detail/R-HSA-3000178) | electronic |
| [HS-GAG biosynthesis](https://reactome.org/content/detail/R-HSA-2022928) | electronic |
| [Integrin cell surface interactions](https://reactome.org/content/detail/R-HSA-216083) | electronic |
| [NCAM1 interactions](https://reactome.org/content/detail/R-HSA-419037) | electronic |
| [Non-integrin membrane-ECM interactions](https://reactome.org/content/detail/R-HSA-3000171) | electronic |

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

**Molecular function:** receptor ligand activity.

**Biological process:** chondrocyte differentiation, cell surface receptor signaling pathway, receptor clustering.

## Clinical significance {#significance}

**Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-01-13.

**Submitter consensus:** conflicting (4 Likely benign, 1 Benign).

**Submission history:** 5 submissions (2021–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Breakthrough Genomics, Breakthrough Genomics | Likely benign | criteria provided, single submitter | not provided |  |
| PreventionGenetics, part of Exact Sciences | Benign | no assertion criteria provided | clinical testing | 2023-03-28 |
| Genome-Nilou Lab | Likely benign | criteria provided, single submitter | clinical testing | 2021-07-14 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-01-13 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2025-08-01 |

## Associated conditions {#conditions}

[congenital myasthenic syndrome 8](https://sugi.bio/atlas/disease/congenital-myasthenic-syndrome-8/).

**Reported phenotype names (ClinVar):** Congenital myasthenic syndrome 8, not provided, AGRN-related disorder, AGRN-related condition, Myasthenic syndrome, congenital, 8, with pre- and postsynaptic defects, MYASTHENIC SYNDROME, CONGENITAL, DUE TO AGRIN DEFICIENCY, none provided.

## Similar variants {#similar}

Related AGRN variant pages (same residue, condition, or type): [AGRN p.Pro396Gln](/variant/agrn-p-pro396gln), [AGRN p.Pro396Leu](/variant/agrn-p-pro396leu), [AGRN c.3632-1G>C](/variant/agrn-c-3632-minus-1g-c), [AGRN p.Arg1671Ter](/variant/agrn-p-arg1671ter), [AGRN p.Arg834Ter](/variant/agrn-p-arg834ter), [AGRN p.Gly1582Arg](/variant/agrn-p-gly1582arg), [AGRN p.Gly1675Ser](/variant/agrn-p-gly1675ser), [AGRN c.1177+4A>G](/variant/agrn-c-1177-plus-4a-g).

### 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 541206). 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.*