# NM_213720.3(CHCHD10):c.273C>A (p.Pro91=)

https://sugi.bio/variant/chchd10-p-pro91

## Summary

**CHCHD10 p.Pro91= (c.273C>A)** is classified **Uncertain significance** in CHCHD10 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-06). Very rare (popmax 8.79e-05%, nfe); Associated with lower motor neuron syndrome with late-adult onset.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs773772416 · 1 submitter · 3 linked conditions · very rare (popmax 8.79e-05%, nfe)

## For patients & families {#patients}

This is a change in the CHCHD10 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to lower motor neuron syndrome with late-adult onset.

*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) | Autosomal dominant |
| Age of onset (of this condition) | Adult |
| Diagnostic panels | CHCHD10 is a diagnostic-grade gene on 14 Genomics England panels |

**Commonly reported features of Lower motor neuron syndrome with late-adult onset** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Distal lower limb muscle weakness — Very frequent (99-80%)
- Hyporeflexia — Frequent (79-30%)
- Areflexia — Frequent (79-30%)
- Gait disturbance — Frequent (79-30%)
- Fasciculations — Frequent (79-30%)
- Elevated circulating creatine kinase concentration — Frequent (79-30%)
- EMG: neuropathic changes — Frequent (79-30%)
- Cold-induced muscle cramps — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0017282/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CHCHD10](https://sugi.bio/atlas/gene/CHCHD10/) |
| Protein change (HGVS p.) | p.Pro91= |
| Coding change (HGVS c.) | c.273C>A |
| MANE Select transcript | [NM_213720](https://www.ncbi.nlm.nih.gov/nuccore/NM_213720) |
| dbSNP | [rs773772416](https://www.ncbi.nlm.nih.gov/snp/rs773772416/) |
| Variant type | single nucleotide variant |
| Location | chr22:23766264-23766264 (GRCh38) |
| ClinVar | [VCV1955643](https://www.ncbi.nlm.nih.gov/clinvar/variation/1955643/) |

**All HGVS expressions:** `NC_000022.10:g.24108451G>T`, `NC_000022.11:g.23766264G>T`, `NG_034223.1:g.6709C>A`, `NG_145141.1:g.855G>T`, `NG_145142.1:g.55G>T`, `NM_001301339.2:c.294C>A`, `NM_213720.3:c.273C>A`, `NR_125755.2:n.318C>A`, `NR_125756.2:n.151C>A`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **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 **acceptor loss** (Δ 0.62) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP -3.007, GERP -2.49 — fast-evolving / accelerated position
- CADD: **PHRED 0.103**. 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 **0.62**, donor loss **0.00**, acceptor gain **0.02**, donor gain **0.00**. Largest is acceptor loss.
- SpliceAI deltas (masked): acceptor loss **0.62**, donor loss **0.00**, acceptor gain **0.02**, donor gain **0.00**.
- Population frequency (gnomAD v4.1): grpmax **8.79e-05%** (nfe) · 1/1,138,218 in the highest group · 1/151,882 alleles overall — very rare (popmax 8.79e-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}

**CHCHD10** population constraint: LOEUF 1.543, pLI 0.00040056, missense-Z -1.0154. *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):

- **mitochondrial disease** — Definitive (AD)
- **frontotemporal dementia and/or amyotrophic lateral sclerosis 2** — Moderate (AD)

## Protein context {#protein}

Residue **91** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 63.01, 7% of residues very-high.

**5 experimental structure(s)** (PDB): [9CWW](https://www.rcsb.org/structure/9CWW), [9OYO](https://www.rcsb.org/structure/9OYO), [9OYQ](https://www.rcsb.org/structure/9OYQ), [9OYS](https://www.rcsb.org/structure/9OYS), [9OYW](https://www.rcsb.org/structure/9OYW).

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

*Describes the biological roles of CHCHD10 (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}

CHCHD10 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Mitochondrial protein import](https://reactome.org/content/detail/R-HSA-1268020) | electronic |

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

**Biological process:** mitochondrion organization, inner mitochondrial membrane organization.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-09-06.

**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 | 2022-09-06 |

## Associated conditions {#conditions}

[lower motor neuron syndrome with late-adult onset](https://sugi.bio/atlas/disease/lower-motor-neuron-syndrome-with-late-adult-onset/), [frontotemporal dementia and/or amyotrophic lateral sclerosis 2](https://sugi.bio/atlas/disease/frontotemporal-dementia-and-or-amyotrophic-lateral-sclerosis-2/), [autosomal dominant mitochondrial myopathy with exercise intolerance](https://sugi.bio/atlas/disease/autosomal-dominant-mitochondrial-myopathy-with-exercise-intolerance/).

**Reported phenotype names (ClinVar):** Lower motor neuron syndrome with late-adult onset, Autosomal dominant mitochondrial myopathy with exercise intolerance, Frontotemporal dementia and/or amyotrophic lateral sclerosis 2, Late-Onset Spinal Motor Neuronopathy (SMAJ), Spinal muscular atrophy, Jokela type, FTDALS2, Myopathy, isolated mitochondrial, autosomal dominant.

## Similar variants {#similar}

Related CHCHD10 variant pages (same residue, condition, or type): [CHCHD10 p.Pro91Thr](/variant/chchd10-p-pro91thr), [CHCHD10 p.Ser59Leu](/variant/chchd10-p-ser59leu), [CHCHD10 c.262-3C>G](/variant/chchd10-c-262-minus-3c-g), [CHCHD10 c.409+1G>A](/variant/chchd10-c-409-plus-1g-a), [CHCHD10 p.Ala31Val](/variant/chchd10-p-ala31val), [CHCHD10 p.Ala35Thr](/variant/chchd10-p-ala35thr), [CHCHD10 p.Ala49Val](/variant/chchd10-p-ala49val), [CHCHD10 p.Arg11Gly](/variant/chchd10-p-arg11gly).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 1955643). 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.*