# NM_000390.4(CHM):c.1565C>A (p.Ser522Ter)

https://sugi.bio/variant/chm-p-ser522ter

## Summary

**CHM p.Ser522Ter (c.1565C>A)** is classified **Pathogenic** in CHM (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-27). No allele count reported in gnomAD v4.1 (AN 1,204,711).

**At a glance:** Pathogenic · review: Single submitter · rsID rs2148126425 · 1 submitter · no allele count reported in gnomAD v4.1 (AN 1,204,711)

## For patients & families {#patients}

This is a change in the CHM gene that is reported as disease-causing, but on limited review, submitted by 1 submitter.

*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 | [CHM](https://sugi.bio/atlas/gene/CHM/) |
| Protein change (HGVS p.) | p.Ser522Ter |
| Coding change (HGVS c.) | c.1565C>A |
| MANE Select transcript | [NM_000390](https://www.ncbi.nlm.nih.gov/nuccore/NM_000390) |
| dbSNP | [rs2148126425](https://www.ncbi.nlm.nih.gov/snp/rs2148126425/) |
| Variant type | single nucleotide variant |
| Location | chrX:85879009-85879009 (GRCh38) |
| ClinVar | [VCV1072298](https://www.ncbi.nlm.nih.gov/clinvar/variation/1072298/) |

**All HGVS expressions:** `LRG_699:g.173554C>A`, `NC_000023.10:g.85134014G>T`, `NC_000023.11:g.85879009G>T`, `NG_009874.2:g.173554C>A`, `NM_000390.4:c.1565C>A`, `NM_001320959.1:c.1121C>A`, `NM_001362517.1:c.1121C>A`, `NM_001362518.2:c.1121C>A`, `NM_001362519.1:c.1121C>A`

## Computational & population evidence {#evidence}

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

- **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 loss** (Δ 0.33) — consistent with the pathogenic call
- Conservation: phyloP 3.913, GERP 0.232, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **nonsense (stop-gain)** — a predicted loss-of-function variant. ClinGen curates **sufficient evidence for haploinsufficiency** in this gene, supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 13 of 15**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 36.0**. 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.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.33**, acceptor gain **0.00**, donor gain **0.00**. Largest is donor loss.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.33**, acceptor gain **0.00**, donor gain **0.00**.
- Pangolin: Δ**0.26** (loss), gain 0.00 / loss 0.26. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency: **no allele count reported in gnomAD v4.1 (AN 1,204,711)** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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}

**CHM** population constraint: ClinGen dosage — haploinsufficiency 3, 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):

- **choroideremia** — Definitive (XL)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 81.05, 66% of residues very-high.

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

*Describes the biological roles of CHM (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:** CHM's established molecular role includes small GTPase binding.


### Pathways affected {#pathways}

CHM participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [RAB GEFs exchange GTP for GDP on RABs](https://reactome.org/content/detail/R-HSA-8876198) | curated |
| [RAB geranylgeranylation](https://reactome.org/content/detail/R-HSA-8873719) | curated |
| [TP53 regulates transcription of several additional cell death genes whose specific roles in p53-dependent apoptosis remain uncertain](https://reactome.org/content/detail/R-HSA-6803205) | curated |

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

**Molecular function:** small GTPase binding.

**Biological process:** protein targeting to membrane, protein geranylgeranylation.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-01-27.

**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 | 2025-01-27 |

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

## Similar variants {#similar}

Related CHM variant pages (same residue, condition, or type): [CHM p.Ser522Leu](/variant/chm-p-ser522leu), [CHM p.Ser522=](/variant/chm-p-ser522), [CHM c.116+1G>A](/variant/chm-c-116-plus-1g-a), [CHM c.116+1G>T](/variant/chm-c-116-plus-1g-t), [CHM c.1166+1G>A](/variant/chm-c-1166-plus-1g-a), [CHM c.1166+1G>C](/variant/chm-c-1166-plus-1g-c), [CHM c.1167-2A>G](/variant/chm-c-1167-minus-2a-g), [CHM c.1244+1G>A](/variant/chm-c-1244-plus-1g-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 1072298). 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.*