# NM_005198.5(CHKB):c.722A>G (p.Asn241Ser)

https://sugi.bio/variant/chkb-p-asn241ser

## Summary

**CHKB p.Asn241Ser (c.722A>G)** is classified **Pathogenic** in CHKB (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-08). AlphaMissense: likely pathogenic (0.7103); Very rare (popmax 0.00333%, amr); Associated with megaconial type congenital muscular dystrophy.

**At a glance:** Pathogenic · review: Single submitter · rsID rs371751084 · 1 submitter · 1 linked condition · AlphaMissense likely pathogenic · very rare (popmax 0.00333%, amr)

## For patients & families {#patients}

This is a change in the CHKB gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to megaconial type congenital muscular dystrophy.

*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) | Infancy, Neonatal |
| Diagnostic panels | CHKB is a diagnostic-grade gene on 12 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0010317/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CHKB](https://sugi.bio/atlas/gene/CHKB/) |
| Protein change (HGVS p.) | p.Asn241Ser |
| Coding change (HGVS c.) | c.722A>G |
| MANE Select transcript | [NM_005198](https://www.ncbi.nlm.nih.gov/nuccore/NM_005198) |
| dbSNP | [rs371751084](https://www.ncbi.nlm.nih.gov/snp/rs371751084/) |
| Variant type | single nucleotide variant |
| Location | chr22:50580372-50580372 (GRCh38) |
| ClinVar | [VCV342172](https://www.ncbi.nlm.nih.gov/clinvar/variation/342172/) |

**All HGVS expressions:** `LRG_855:g.7628A>G`, `LRG_855t1:c.722A>G`, `NC_000022.10:g.51018801T>C`, `NC_000022.11:g.50580372T>C`, `NG_012643.1:g.3296A>G`, `NG_029213.1:g.7628A>G`, `NM_005198.5:c.722A>G`, `NR_027928.2:n.940A>G`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- AlphaMissense **likely pathogenic** (0.7103) — concordant with the pathogenic call
- REVEL 0.638 (indeterminate)
- SaProt LLR -12.936 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this damaging; REVEL makes no call
- SpliceAI predicts **acceptor gain** (Δ 0.49) — consistent with the pathogenic call
- Conservation: phyloP 7.804, GERP 2.35, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 34.0**. 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 1.03** across the covering region of the MANE Select transcript (50,579,184–50,582,781), spanning 3,597 bp. Chi-square p 0.53. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.17**, donor loss **0.04**, acceptor gain **0.49**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.17**, donor loss **0.04**, acceptor gain **0.49**, donor gain **0.00**.
- Population frequency (gnomAD v4.1): grpmax **0.00333%** (amr) · FAF95 0.00111% · FAF99 0.0009% · 2/60,004 in the highest group · 28/1,613,892 alleles overall — very rare (popmax 0.00333%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.00333% | 30,002 |
| South Asian | 0.00329% | 30,358 |
| Remaining individuals (not grpmax-eligible) | 0.0032% | 31,244 |
| European (non-Finnish) | 0.00169% | 59,002 |
| African / African-American | 0.00134% | 74,892 |

*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}

**CHKB** population constraint: LOEUF 1.015, pLI 5.1371e-13, missense-Z -0.14666; 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.*

## Protein context {#protein}

Residue **241** lies in a UniProt-annotated variant site (in mdcmc; loss of choline kinase activity; decreased amount of phosphatidylcholine in patients cells); a UniProt-annotated variant site (in mdcmc).

AlphaFold model confidence (whole protein): pLDDT 86.54, 69% of residues very-high.

**3 experimental structure(s)** (PDB): [2IG7](https://www.rcsb.org/structure/2IG7), [3FEG](https://www.rcsb.org/structure/3FEG), [3LQ3](https://www.rcsb.org/structure/3LQ3).

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

*Describes the biological roles of CHKB (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:** CHKB's established molecular role includes choline kinase activity.


### Pathways affected {#pathways}

CHKB participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Synthesis of PC](https://reactome.org/content/detail/R-HSA-1483191) | curated |
| [Synthesis of PE](https://reactome.org/content/detail/R-HSA-1483213) | curated |

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

**Molecular function:** choline kinase activity, ethanolamine kinase activity.

**Biological process:** phosphatidylethanolamine biosynthetic process.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-09-08.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-09-08 |

## Associated conditions {#conditions}

[megaconial type congenital muscular dystrophy](https://sugi.bio/atlas/disease/megaconial-type-congenital-muscular-dystrophy/).

**Reported phenotype names (ClinVar):** Megaconial type congenital muscular dystrophy, MUSCULAR DYSTROPHY, CONGENITAL, WITH MITOCHONDRIAL STRUCTURAL ABNORMALITIES, CHKB-Related Muscle Diseases, CHKB-Related Muscular Dystrophy.

## Similar variants {#similar}

Related CHKB variant pages (same residue, condition, or type): [CHKB p.Gln51Ter](/variant/chkb-p-gln51ter), [CHKB c.*208T>G](/variant/chkb-c-star-208t-g), [CHKB p.Ala361Val](/variant/chkb-p-ala361val), [CHKB p.Arg344Trp](/variant/chkb-p-arg344trp), [CHKB p.Arg62Cys](/variant/chkb-p-arg62cys), [CHKB p.Gln309Glu](/variant/chkb-p-gln309glu), [CHKB p.Glu214Asp](/variant/chkb-p-glu214asp), [CHKB p.Glu336Lys](/variant/chkb-p-glu336lys).

### 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 342172). 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.*