# NM_018397.5(CHDH):c.1234C>T (p.Arg412Trp)

https://sugi.bio/variant/chdh-p-arg412trp

## Summary

**CHDH p.Arg412Trp (c.1234C>T)** is classified **Uncertain significance** in CHDH (ClinVar, Single submitter, 2 submitters; last evaluated 2024-03-31). AlphaMissense: ambiguous (0.4149); Very rare (popmax 0.0022%, sas).

**At a glance:** Uncertain significance · review: Single submitter · 2 submitters · AlphaMissense ambiguous · very rare (popmax 0.0022%, sas)

## For patients & families {#patients}

This is a change in the CHDH gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 submitters.

*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 | [CHDH](https://sugi.bio/atlas/gene/CHDH/) |
| Protein change (HGVS p.) | p.Arg412Trp |
| Coding change (HGVS c.) | c.1234C>T |
| MANE Select transcript | [NM_018397](https://www.ncbi.nlm.nih.gov/nuccore/NM_018397) |
| Variant type | single nucleotide variant |
| Location | chr3:53819561-53819561 (GRCh38) |
| ClinVar | [VCV3266930](https://www.ncbi.nlm.nih.gov/clinvar/variation/3266930/) |

**All HGVS expressions:** `NC_000003.11:g.53853588G>A`, `NC_000003.12:g.53819561G>A`, `NG_028042.1:g.31833C>T`, `NM_018397.5:c.1234C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **ambiguous** (0.4149) — no call either way
- REVEL 0.336 (indeterminate)
- SaProt LLR -12.81 (damaging)
- SpliceAI predicts **donor loss** (Δ 0.49) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 5.1, GERP 1.79, phastCons 1 — highly conserved
- CADD: **PHRED 28.8**. 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 0.99** across the covering region of the MANE Select transcript (53,817,780–53,824,008), spanning 6,228 bp. Chi-square p 0.86. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.01**, donor loss **0.49**, acceptor gain **0.01**, donor gain **0.00**. Largest is donor loss, 29 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Pangolin: Δ**0.26** (loss), gain 0.02 / 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 (gnomAD v4.1): grpmax **0.0022%** (sas) · FAF95 0.000365% · FAF99 0.000137% · 2/90,864 in the highest group · 9/1,612,252 alleles overall — very rare (popmax 0.0022%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.00321% | 31,200 |
| South Asian (grpmax) | 0.0022% | 45,432 |
| African / African-American | 0.00134% | 74,804 |
| European (non-Finnish) | 0.000339% | 294,777 |

Remaining individuals 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}

**CHDH** population constraint: LOEUF 1.092, pLI 4.2832e-12, missense-Z -0.45895. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 92.84, 90% of residues very-high.

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

*Describes the biological roles of CHDH (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.*


### Pathways affected {#pathways}

CHDH participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Choline catabolism](https://reactome.org/content/detail/R-HSA-6798163) | curated |

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-03-31.

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

**Submission history:** 2 submissions (2024); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-03-31 |
| Dr. Peter K. Rogan Lab, Western University |  | no classification provided | in vitro |  |

**Reported phenotype names (ClinVar):** not specified, Cervical cancer, AllHighlyPenetrant.

## Similar variants {#similar}

Related CHDH variant pages (same residue, condition, or type): [CHDH p.Pro396Leu](/variant/chdh-p-pro396leu), [CHDH c.704-3C>T](/variant/chdh-c-704-minus-3c-t), [CHDH p.Gly235=](/variant/chdh-p-gly235), [CHDH p.Val45=](/variant/chdh-p-val45), [CHDH p.Ala13Val](/variant/chdh-p-ala13val), [CHDH p.Ala170Thr](/variant/chdh-p-ala170thr), [CHDH p.Ala177Thr](/variant/chdh-p-ala177thr), [CHDH p.Ala240Val](/variant/chdh-p-ala240val).

### 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 3266930). 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.*