# NM_203298.3(CHCHD1):c.248C>T (p.Ala83Val)

https://sugi.bio/variant/chchd1-p-ala83val

## Summary

**CHCHD1 p.Ala83Val (c.248C>T)** is classified **Uncertain significance** in CHCHD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-21). AlphaMissense: likely benign (0.1); Very rare (popmax 8.49e-05%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely benign · very rare (popmax 8.49e-05%, nfe)

## For patients & families {#patients}

This is a change in the CHCHD1 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 | [CHCHD1](https://sugi.bio/atlas/gene/CHCHD1/) |
| Protein change (HGVS p.) | p.Ala83Val |
| Coding change (HGVS c.) | c.248C>T |
| MANE Select transcript | [NM_203298](https://www.ncbi.nlm.nih.gov/nuccore/NM_203298) |
| Variant type | single nucleotide variant |
| Location | chr10:73783078-73783078 (GRCh38) |
| ClinVar | [VCV3491887](https://www.ncbi.nlm.nih.gov/clinvar/variation/3491887/) |

**All HGVS expressions:** `NC_000010.10:g.75542836C>T`, `NC_000010.11:g.73783078C>T`, `NM_203298.3:c.248C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.1)
- REVEL 0.048 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -5.956 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 2.235, GERP 0.507, phastCons 0.976 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 20.7**. 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 0.97** across the covering region of the MANE Select transcript (73,782,076–73,783,184), spanning 1,108 bp. Chi-square p 0.7. 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 (C>A, Δ0.25 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 **8.49e-05%** (nfe) · 1/1,178,274 in the highest group · 1/1,458,858 alleles overall — very rare (popmax 8.49e-05%, nfe).

*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}

**CHCHD1** population constraint: LOEUF 1.628, pLI 0.00011307, missense-Z 0.5511. *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 **83** lies in the chch domain; an α-helix.

AlphaFold model confidence (whole protein): pLDDT 92.51, 81% of residues very-high.

**64 experimental structure(s)** (PDB): [3J9M](https://www.rcsb.org/structure/3J9M), [6NU2](https://www.rcsb.org/structure/6NU2), [6NU3](https://www.rcsb.org/structure/6NU3), [6RW4](https://www.rcsb.org/structure/6RW4), [6RW5](https://www.rcsb.org/structure/6RW5), [6VLZ](https://www.rcsb.org/structure/6VLZ).

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

*Describes the biological roles of CHCHD1 (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:** CHCHD1's established molecular role includes RNA binding. p.Ala83Val falls in the chch domain.


### Pathways affected {#pathways}

CHCHD1 participates in **4 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Mitochondrial ribosome-associated quality control](https://reactome.org/content/detail/R-HSA-9937383) | curated |
| [Mitochondrial translation termination](https://reactome.org/content/detail/R-HSA-5419276) | curated |
| [Mitochondrial translation elongation](https://reactome.org/content/detail/R-HSA-5389840) | electronic |
| [Mitochondrial translation initiation](https://reactome.org/content/detail/R-HSA-5368286) | electronic |

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

**Molecular function:** RNA binding.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-11-21.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-11-21 |

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

## Similar variants {#similar}

Related CHCHD1 variant pages (same residue, condition, or type): [CHCHD1 p.Arg32Pro](/variant/chchd1-p-arg32pro), [CHCHD1 p.Arg7Trp](/variant/chchd1-p-arg7trp), [CHCHD1 p.Arg9Leu](/variant/chchd1-p-arg9leu), [CHCHD1 p.Asn24Ser](/variant/chchd1-p-asn24ser), [CHCHD1 p.Gln90Arg](/variant/chchd1-p-gln90arg), [CHCHD1 p.Glu95Lys](/variant/chchd1-p-glu95lys), [CHCHD1 p.Ile70Asn](/variant/chchd1-p-ile70asn), [CHCHD1 p.Leu10Arg](/variant/chchd1-p-leu10arg).

### 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 3491887). 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.*