# NM_000751.3(CHRND):c.1237C>A (p.Arg413Ser)

https://sugi.bio/variant/chrnd-p-arg413ser

## Summary

**CHRND p.Arg413Ser (c.1237C>A)** is classified **Uncertain significance** in CHRND (ClinVar, Single submitter, 1 submitter; last evaluated 2017-10-02). AlphaMissense: ambiguous (0.4727); Very rare (popmax 8.47e-05%, nfe); Associated with lethal multiple pterygium syndrome.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs1242056715 · 1 submitter · 1 linked condition · AlphaMissense ambiguous · very rare (popmax 8.47e-05%, nfe)

## For patients & families {#patients}

This is a change in the CHRND gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to lethal multiple pterygium syndrome.

*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/0003834/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CHRND](https://sugi.bio/atlas/gene/CHRND/) |
| Protein change (HGVS p.) | p.Arg413Ser |
| Coding change (HGVS c.) | c.1237C>A |
| MANE Select transcript | [NM_000751](https://www.ncbi.nlm.nih.gov/nuccore/NM_000751) |
| dbSNP | [rs1242056715](https://www.ncbi.nlm.nih.gov/snp/rs1242056715/) |
| Variant type | single nucleotide variant |
| Location | chr2:232534120-232534120 (GRCh38) |
| ClinVar | [VCV534531](https://www.ncbi.nlm.nih.gov/clinvar/variation/534531/) |

**All HGVS expressions:** `NC_000002.11:g.233398830C>A`, `NC_000002.12:g.232534120C>A`, `NG_008028.1:g.12909C>A`, `NM_000751.3:c.1237C>A`, `NM_001256657.2:c.1192C>A`, `NM_001311195.2:c.655C>A`, `NM_001311196.2:c.934C>A`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense and REVEL make no call here — the available evidence is described below.

- AlphaMissense **ambiguous** (0.4727) — no call either way
- REVEL 0.466 (indeterminate)
- SaProt LLR -5.608 (tolerated)
- Conservation: phyloP 7.58, GERP 1.86, phastCons 1 — highly conserved
- CADD: **PHRED 23.3**. 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.*
- Regional missense constraint: **o/e 0.94** across the covering region of the MANE Select transcript (232,526,216–232,535,309), spanning 9,093 bp. Chi-square p 0.12. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (C>T, Δ0.97 donor 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 **8.47e-05%** (nfe) · 1/1,180,032 in the highest group · 1/1,461,750 alleles overall — very rare (popmax 8.47e-05%, nfe).

*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}

**CHRND** population constraint: LOEUF 0.848, pLI 4.9651e-09, missense-Z 1.0189. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 84.21, 51% of residues very-high.

**25 experimental structure(s)** (PDB): [9DMG](https://www.rcsb.org/structure/9DMG), [9DMH](https://www.rcsb.org/structure/9DMH), [9DMJ](https://www.rcsb.org/structure/9DMJ), [9DMK](https://www.rcsb.org/structure/9DMK), [9DML](https://www.rcsb.org/structure/9DML), [9DMQ](https://www.rcsb.org/structure/9DMQ).

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

*Describes the biological roles of CHRND (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:** CHRND's established molecular role includes transmitter-gated monoatomic ion channel activity involved in regulation of postsynaptic membrane potential.


### Pathways affected {#pathways}

CHRND participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Highly sodium permeable postsynaptic acetylcholine nicotinic receptors](https://reactome.org/content/detail/R-HSA-629587) | curated |

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

**Molecular function:** transmitter-gated monoatomic ion channel activity involved in regulation of postsynaptic membrane potential.

**Biological process:** skeletal muscle tissue growth, musculoskeletal movement.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2017-10-02.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2017-10-02 |

## Associated conditions {#conditions}

[lethal multiple pterygium syndrome](https://sugi.bio/atlas/disease/lethal-multiple-pterygium-syndrome/).

**Reported phenotype names (ClinVar):** Lethal multiple pterygium syndrome.

## Similar variants {#similar}

Related CHRND variant pages (same residue, condition, or type): [CHRND p.Arg413Cys](/variant/chrnd-p-arg413cys), [CHRND p.Arg413His](/variant/chrnd-p-arg413his), [CHRND p.Arg413Leu](/variant/chrnd-p-arg413leu), [CHRND c.1252+1G>A](/variant/chrnd-c-1252-plus-1g-a), [CHRND c.821-2A>C](/variant/chrnd-c-821-minus-2a-c), [CHRND c.933-2A>G](/variant/chrnd-c-933-minus-2a-g), [CHRND p.Arg336Gln](/variant/chrnd-p-arg336gln), [CHRND p.Arg43Trp](/variant/chrnd-p-arg43trp).

### 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 534531). 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.*