# NM_198576.4(AGRN):c.1929C>T (p.Cys643=)

https://sugi.bio/variant/agrn-p-cys643

## Summary

**AGRN p.Cys643= (c.1929C>T)** is classified **Conflicting classifications of pathogenicity** in AGRN (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-11-18). Ultra-rare (popmax 0.0249%, nfe); Associated with congenital myasthenic syndrome 8.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs371304780 · 3 submitters · 1 linked condition · ultra-rare (popmax 0.0249%, nfe)

## For patients & families {#patients}

This is a change in the AGRN gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 3 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.Cys643= |
| Coding change (HGVS c.) | c.1929C>T |
| MANE Select transcript | [NM_198576](https://www.ncbi.nlm.nih.gov/nuccore/NM_198576) |
| dbSNP | [rs371304780](https://www.ncbi.nlm.nih.gov/snp/rs371304780/) |
| Variant type | single nucleotide variant |
| Location | chr1:1043953-1043953 (GRCh38) |
| ClinVar | [VCV1132750](https://www.ncbi.nlm.nih.gov/clinvar/variation/1132750/) |

**All HGVS expressions:** `LRG_198:g.28831C>T`, `NC_000001.10:g.979333C>T`, `NC_000001.11:g.1043953C>T`, `NG_016346.1:g.28831C>T`, `NM_001305275.2:c.1929C>T`, `NM_001364727.2:c.1614C>T`, `NM_198576.4:c.1929C>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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor gain** (Δ 0.27) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP -6.678, GERP -0.896 — fast-evolving / accelerated position
- CADD: **PHRED 6.772**. 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 deltas (raw): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.27**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.27**.
- Population frequency (gnomAD v4.1): grpmax **0.0249%** (nfe) · FAF95 0.0226% · FAF99 0.0217% · 294/1,178,712 in the highest group · 316/1,605,948 alleles overall — ultra-rare (popmax 0.0249%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.0249% | 4,009 |
| Remaining individuals (not grpmax-eligible) | 0.0241% | 4,146 |
| Admixed American | 0.00503% | 19,876 |
| African / African-American | 0.00401% | 24,952 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.00339% | 29,534 |

*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}

Residue **643** lies in the kazal-like 7 domain; a disulfide bond.

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. p.Cys643= falls in the kazal-like 7 domain. 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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2025-11-18.

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

**Submission history:** 3 submissions (2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Revvity Omics, Revvity | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-06-20 |
| Dr. Peter K. Rogan Lab, Western University |  | no classification provided | in vitro |  |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-11-18 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Congenital myasthenic syndrome 8, Uterine corpus endometrial carcinoma, MYASTHENIC SYNDROME, CONGENITAL, DUE TO AGRIN DEFICIENCY, Myasthenic syndrome, congenital, 8, with pre- and postsynaptic defects.

## Similar variants {#similar}

Related AGRN variant pages (same residue, condition, or type): [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), [AGRN c.1384+6C>T](/variant/agrn-c-1384-plus-6c-t), [AGRN c.4879+4G>A](/variant/agrn-c-4879-plus-4g-a).

### 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 1132750). 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.*