# NM_005199.5(CHRNG):c.1551C>T (p.Asp517=)

https://sugi.bio/variant/chrng-p-asp517

## Summary

**CHRNG p.Asp517= (c.1551C>T)** is classified **Likely benign** in CHRNG (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-09). Ultra-rare (popmax 0.0329%, mid).

**At a glance:** Likely benign · review: Multiple submitters · rsID rs754319350 · 2 submitters · ultra-rare (popmax 0.0329%, mid)

## For patients & families {#patients}

This is a change in the CHRNG gene that is classified as likely benign — not considered disease-causing, submitted by 2 submitters.

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

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CHRNG](https://sugi.bio/atlas/gene/CHRNG/) |
| Protein change (HGVS p.) | p.Asp517= |
| Coding change (HGVS c.) | c.1551C>T |
| MANE Select transcript | [NM_005199](https://www.ncbi.nlm.nih.gov/nuccore/NM_005199) |
| dbSNP | [rs754319350](https://www.ncbi.nlm.nih.gov/snp/rs754319350/) |
| Variant type | single nucleotide variant |
| Location | chr2:232545713-232545713 (GRCh38) |
| ClinVar | [VCV790529](https://www.ncbi.nlm.nih.gov/clinvar/variation/790529/) |

**All HGVS expressions:** `LRG_1275:g.11022C>T`, `LRG_1275t1:c.1551C>T`, `NC_000002.11:g.233410423C>T`, `NC_000002.12:g.232545713C>T`, `NG_012954.2:g.11022C>T`, `NM_005199.5:c.1551C>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 0.166, GERP -0.488, phastCons 0.976 — weakly conserved position
- CADD: **PHRED 7.69**. 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>G, Δ0.50 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 **0.0329%** (mid) · FAF95 0.0109% · FAF99 0.0102% · 2/6,084 in the highest group · 191/1,614,042 alleles overall — ultra-rare (popmax 0.0329%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Finnish (not grpmax-eligible) | 0.0453% | 2,205 |
| Middle Eastern (grpmax) | 0.0329% | 3,042 |
| European (non-Finnish) | 0.0125% | 7,973 |
| Remaining individuals (not grpmax-eligible) | 0.0112% | 8,927 |
| Admixed American | 0.00833% | 12,000 |

Finnish 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}

**CHRNG** population constraint: LOEUF 1.286, pLI 4.4206e-25, missense-Z 0.9905. *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):

- **CHRNG-associated hypo-akinesia disorder of prenatal onset** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 81.91, 47% of residues very-high.

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

*Describes the biological roles of CHRNG (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.*


### Pathways affected {#pathways}

CHRNG 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 |

## Clinical significance {#significance}

**Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-01-09.

**Submitter consensus:** unanimous (2/2 Likely benign).

**Submission history:** 2 submissions (2026); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Breakthrough Genomics, Breakthrough Genomics | Likely benign | criteria provided, single submitter | not provided |  |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-01-09 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related CHRNG variant pages (same residue, condition, or type): [CHRNG c.1380+1G>A](/variant/chrng-c-1380-plus-1g-a), [CHRNG c.350+2T>C](/variant/chrng-c-350-plus-2t-c), [CHRNG c.351-2A>G](/variant/chrng-c-351-minus-2a-g), [CHRNG c.56-1G>A](/variant/chrng-c-56-minus-1g-a), [CHRNG c.805+1G>A](/variant/chrng-c-805-plus-1g-a), [CHRNG p.Arg239Cys](/variant/chrng-p-arg239cys), [CHRNG p.Arg341Ter](/variant/chrng-p-arg341ter), [CHRNG p.Arg46Ter](/variant/chrng-p-arg46ter).

### 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 790529). 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.*