# NM_000390.4(CHM):c.1246T>C (p.Cys416Arg)

https://sugi.bio/variant/chm-p-cys416arg

## Summary

**CHM p.Cys416Arg (c.1246T>C)** is classified **Uncertain significance** in CHM (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-17). AlphaMissense: likely pathogenic (0.9902); No allele count reported in gnomAD v4.1 (AN 1,116,930).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs1926267075 · 1 submitter · AlphaMissense likely pathogenic · no allele count reported in gnomAD v4.1 (AN 1,116,930)

## 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.

*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.Cys416Arg |
| Coding change (HGVS c.) | c.1246T>C |
| MANE Select transcript | [NM_000390](https://www.ncbi.nlm.nih.gov/nuccore/NM_000390) |
| dbSNP | [rs1926267075](https://www.ncbi.nlm.nih.gov/snp/rs1926267075/) |
| Variant type | single nucleotide variant |
| Location | chrX:85901187-85901187 (GRCh38) |
| ClinVar | [VCV933944](https://www.ncbi.nlm.nih.gov/clinvar/variation/933944/) |

**All HGVS expressions:** `LRG_699:g.151376T>C`, `LRG_699t1:c.1246T>C`, `NC_000023.10:g.85156192A>G`, `NC_000023.11:g.85901187A>G`, `NG_009874.2:g.151376T>C`, `NM_000390.4:c.1246T>C`, `NM_001320959.1:c.802T>C`, `NM_001362517.1:c.802T>C`, `NM_001362518.2:c.802T>C`, `NM_001362519.1:c.802T>C`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.9902)
- REVEL 0.41 (indeterminate)
- SaProt LLR -13.941 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this damaging; REVEL makes no call
- Conservation: phyloP 10.936, GERP 1.85, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 3%** most-pathogenic-predicted substitutions in CHM (of 3,837 modeled).
- CADD: **PHRED 26.3**. 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: **below the reporting threshold**. This position is scored for a different substitution (A>T, Δ0.21 acceptor loss), 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: **no allele count reported in gnomAD v4.1 (AN 1,116,930)** — 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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-10-17.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-10-17 |

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

## Similar variants {#similar}

Related CHM variant pages (same residue, condition, or type): [CHM p.Cys416=](/variant/chm-p-cys416), [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), [CHM c.1244+2T>A](/variant/chm-c-1244-plus-2t-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 933944). 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.*