# NM_000390.4(CHM):c.17C>A (p.Pro6His)

https://sugi.bio/variant/chm-p-pro6his

## Summary

**CHM p.Pro6His (c.17C>A)** is classified **Uncertain significance** in CHM (ClinVar, No assertion criteria, 1 submitter; last evaluated 2025-04-02). AlphaMissense: likely pathogenic (0.9102); Very rare (popmax 0.00178%, sas); Associated with choroideremia.

**At a glance:** Uncertain significance · review: No assertion criteria · 1 submitter · 1 linked condition · AlphaMissense likely pathogenic · very rare (popmax 0.00178%, sas)

## For patients & families {#patients}

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

*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) | X-linked recessive |
| Age of onset (of this condition) | Adolescent, Adult, Childhood |
| Prevalence | 1-9 / 100 000 (Europe) |
| Clinical trials | 32 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | CHM is a diagnostic-grade gene on 3 Genomics England panels |

**Commonly reported features of Choroideremia** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Visual impairment — Very frequent (99-80%)
- Abnormal electroretinogram — Very frequent (99-80%)
- Myopia — Very frequent (99-80%)
- Nyctalopia — Very frequent (99-80%)
- Abnormality of retinal pigmentation — Very frequent (99-80%)
- Progressive visual loss — Frequent (79-30%)
- Constriction of peripheral visual field — Frequent (79-30%)
- Choroideremia — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0006061/index) · [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.Pro6His |
| Coding change (HGVS c.) | c.17C>A |
| MANE Select transcript | [NM_000390](https://www.ncbi.nlm.nih.gov/nuccore/NM_000390) |
| Variant type | single nucleotide variant |
| Location | chrX:86047516-86047516 (GRCh38) |
| ClinVar | [VCV4064678](https://www.ncbi.nlm.nih.gov/clinvar/variation/4064678/) |

**All HGVS expressions:** `LRG_699:g.5047C>A`, `LRG_699t1:c.17C>A`, `LRG_699t2:c.17C>A`, `NC_000023.10:g.85302520G>T`, `NC_000023.11:g.86047516G>T`, `NG_009874.2:g.5047C>A`, `NM_000390.4:c.17C>A`, `NM_001145414.4:c.17C>A`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **damaging** — a triage signal, not a reclassification.

- AlphaMissense **likely pathogenic** (0.9102)
- REVEL 0.434 (indeterminate)
- SaProt LLR -12.017 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this damaging; REVEL makes no call
- Conservation: phyloP 6.095, GERP 1.01, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 24.3**. 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 0.95** across the covering region of the MANE Select transcript (85,864,633–86,047,532), spanning 182,899 bp. Chi-square p 0.28. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.00178%** (sas) · FAF95 0.000716% · FAF99 0.000566% · 1/56,196 in the highest group · 13/1,094,139 alleles overall — very rare (popmax 0.00178%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.00178% | 56,196 |
| European (non-Finnish) | 0.00134% | 74,416 |

*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}

**Uncertain significance** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2025-04-02.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Natera, Inc. | Uncertain significance | no assertion criteria provided | clinical testing | 2025-04-02 |

## Associated conditions {#conditions}

[choroideremia](https://sugi.bio/atlas/disease/choroideremia/).

**Reported phenotype names (ClinVar):** Choroideremia, Chorioretinal scalloped atrophy.

## Same-residue context {#hotspot}

Residue **6** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [CHM p.Pro6fs](/variant/chm-p-pro6fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related CHM variant pages (same residue, condition, or type): [CHM p.Pro6Arg](/variant/chm-p-pro6arg), [CHM p.Pro6=](/variant/chm-p-pro6), [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.1350-1G>A](/variant/chm-c-1350-minus-1g-a), [CHM c.1413+1G>T](/variant/chm-c-1413-plus-1g-t).

### 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 4064678). 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.*