# NM_005198.5(CHKB):c.263C>T (p.Pro88Leu)

https://sugi.bio/variant/chkb-p-pro88leu

## Summary

**CHKB p.Pro88Leu (c.263C>T)** is classified **Conflicting classifications of pathogenicity** in CHKB (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-01-02). AlphaMissense: ambiguous (0.37); Ultra-rare (popmax 0.0451%, sas); Associated with megaconial type congenital muscular dystrophy.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs146163970 · 4 submitters · 1 linked condition · AlphaMissense ambiguous · ultra-rare (popmax 0.0451%, sas)

## For patients & families {#patients}

This is a change in the CHKB gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 4 submitters, 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.Pro88Leu |
| Coding change (HGVS c.) | c.263C>T |
| MANE Select transcript | [NM_005198](https://www.ncbi.nlm.nih.gov/nuccore/NM_005198) |
| dbSNP | [rs146163970](https://www.ncbi.nlm.nih.gov/snp/rs146163970/) |
| Variant type | single nucleotide variant |
| Location | chr22:50582319-50582319 (GRCh38) |
| ClinVar | [VCV447030](https://www.ncbi.nlm.nih.gov/clinvar/variation/447030/) |

**All HGVS expressions:** `LRG_855:g.5681C>T`, `LRG_855t1:c.263C>T`, `NC_000022.10:g.51020748G>A`, `NC_000022.11:g.50582319G>A`, `NG_012643.1:g.1349C>T`, `NG_029213.1:g.5681C>T`, `NM_005198.5:c.263C>T`, `NR_027928.2:n.481C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **ambiguous** (0.37) — no call either way
- REVEL 0.378 (indeterminate)
- SaProt LLR -11.96 (damaging)
- Conservation: phyloP 9.521, GERP 2.25, phastCons 1 — highly conserved
- CADD: **PHRED 29.9**. 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: **below the reporting threshold**. This position is scored for a different substitution (G>T, Δ0.94 acceptor 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 **0.0451%** (sas) · FAF95 0.0338% · FAF99 0.0299% · 39/86,546 in the highest group · 369/1,583,094 alleles overall — ultra-rare (popmax 0.0451%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Ashkenazi Jewish (not grpmax-eligible) | 0.363% | 276 |
| South Asian (grpmax) | 0.0451% | 2,219 |
| Finnish (not grpmax-eligible) | 0.0284% | 3,518 |
| Remaining individuals (not grpmax-eligible) | 0.0245% | 4,081 |
| Middle Eastern | 0.0216% | 4,624 |
| European (non-Finnish) | 0.0161% | 6,209 |
| Admixed American | 0.00359% | 27,833 |
| African / African-American | 0.00269% | 37,218 |

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}

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

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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2026-01-02.

**Submitter consensus:** conflicting (3 Uncertain significance, 1 Likely benign).

**Submission history:** 4 submissions (2016–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Athena Diagnostics | Uncertain significance | criteria provided, single submitter | clinical testing | 2016-06-07 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-04-18 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-01-02 |
| Revvity Omics, Revvity | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-03-17 |

## 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, not specified, AllHighlyPenetrant, CHKB-Related Muscle Diseases, CHKB-Related Muscular Dystrophy, MUSCULAR DYSTROPHY, CONGENITAL, WITH MITOCHONDRIAL STRUCTURAL ABNORMALITIES.

## Similar variants {#similar}

Related CHKB variant pages (same residue, condition, or type): [CHKB p.Pro88Ser](/variant/chkb-p-pro88ser), [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).

### 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 447030). 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.*