# NM_020247.5(COQ8A):c.993C>T (p.Phe331=)

https://sugi.bio/variant/coq8a-p-phe331

## Summary

**COQ8A p.Phe331= (c.993C>T)** is classified **Benign/Likely benign** in COQ8A (ClinVar, Multiple submitters, 20 submitters; last evaluated 2026-06-01). Low-frequency (popmax 2.16%, nfe); Associated with coenzyme Q10 deficiency.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs41303129 · 20 submitters · 3 linked conditions · low-frequency (popmax 2.16%, nfe)

## For patients & families {#patients}

This is a change in the COQ8A gene that is classified as benign/likely benign — not considered disease-causing, submitted by 20 submitters, and is linked to coenzyme Q10 deficiency.

*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.*

|  |  |
| --- | --- |
| Clinical trials | 1 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0010423/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [COQ8A](https://sugi.bio/atlas/gene/COQ8A/) |
| Protein change (HGVS p.) | p.Phe331= |
| Coding change (HGVS c.) | c.993C>T |
| MANE Select transcript | [NM_020247](https://www.ncbi.nlm.nih.gov/nuccore/NM_020247) |
| dbSNP | [rs41303129](https://www.ncbi.nlm.nih.gov/snp/rs41303129/) |
| Variant type | single nucleotide variant |
| Location | chr1:226982947-226982947 (GRCh38) |
| ClinVar | [VCV3645](https://www.ncbi.nlm.nih.gov/clinvar/variation/3645/) |

**All HGVS expressions:** `LRG_1092:g.90412C>T`, `LRG_1092t1:c.993C>T`, `NC_000001.10:g.227170648C>T`, `NC_000001.11:g.226982947C>T`, `NG_012825.2:g.90412C>T`, `NM_020247.5:c.993C>T`

## 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 (below), not from a missing predictor score.
- Conservation: phyloP -15.176, GERP -4.98 — fast-evolving / accelerated position
- CADD: **PHRED 0.211**. 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: **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 **2.16%** (nfe) · FAF95 2.13% · FAF99 2.12% · 25,397/1,178,484 in the highest group · 30,448/1,609,616 alleles overall — low-frequency (popmax 2.16%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Finnish (not grpmax-eligible) | 2.53% | 39 |
| European (non-Finnish) (grpmax) | 2.16% | 46 |
| Ashkenazi Jewish (not grpmax-eligible) | 2.06% | 49 |
| Remaining individuals (not grpmax-eligible) | 1.74% | 57 |
| Middle Eastern | 1.55% | 65 |
| Amish (not grpmax-eligible) | 1.21% | 83 |
| South Asian | 1.1% | 91 |
| Admixed American | 0.71% | 141 |
| African / African-American | 0.329% | 304 |
| East Asian | 0.00897% | 11,152 |

Finnish 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}

**COQ8A** population constraint: LOEUF 0.999, pLI 7.6305e-15, missense-Z -0.50193. *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 **331** lies in the protein kinase domain; a β-strand.

AlphaFold model confidence (whole protein): pLDDT 70.65, 33% of residues very-high.

**4 experimental structure(s)** (PDB): [4PED](https://www.rcsb.org/structure/4PED), [5I35](https://www.rcsb.org/structure/5I35), [7UDP](https://www.rcsb.org/structure/7UDP), [7UDQ](https://www.rcsb.org/structure/7UDQ).

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

*Describes the biological roles of COQ8A (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:** COQ8A's established molecular role includes kinase activity. p.Phe331= falls in the protein kinase domain.


### Pathways affected {#pathways}

COQ8A participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Ubiquinol biosynthesis](https://reactome.org/content/detail/R-HSA-2142789) | curated |

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

**Molecular function:** kinase activity, ADP binding.

**Biological process:** ubiquinone biosynthetic process, phosphorylation.

## Clinical significance {#significance}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-06-01.

**Submitter consensus:** conflicting (14 Benign, 3 Likely benign, 1 Pathogenic, 1 not provided, 1 benign).

**Submission history:** 20 submissions (2008–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Mayo Clinic Laboratories, Mayo Clinic | Benign | no assertion criteria provided | clinical testing | 2016-02-25 |
| Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | Benign | no assertion criteria provided | clinical testing |  |
| Molecular Genetics, Royal Melbourne Hospital | Benign | criteria provided, single submitter | clinical testing | 2023-06-06 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-26 |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2008-03-01 |
| Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Benign | criteria provided, single submitter | clinical testing | 2016-03-29 |
| Illumina Laboratory Services, Illumina | Benign | criteria provided, single submitter | clinical testing | 2018-03-06 |
| Clinical Genetics, Academic Medical Center | Benign | no assertion criteria provided | clinical testing |  |
| Genome Diagnostics Laboratory, University Medical Center Utrecht | Likely benign | no assertion criteria provided | clinical testing |  |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2018-12-04 |
| Fulgent Genetics, Fulgent Genetics | Benign | criteria provided, single submitter | clinical testing | 2021-07-20 |
| ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Benign | criteria provided, single submitter | clinical testing | 2023-06-28 |
| Eurofins Ntd Llc (ga) | Benign | criteria provided, single submitter | clinical testing | 2014-12-17 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-02-02 |
| CeGaT Center for Human Genetics Tuebingen | Benign | criteria provided, single submitter | clinical testing | 2026-06-01 |
| Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia | Benign | criteria provided, single submitter | clinical testing | 2015-04-12 |
| Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Benign | criteria provided, single submitter | research |  |
| GeneReviews | not provided | no classification provided | literature only |  |
| Breakthrough Genomics, Breakthrough Genomics | Likely benign | criteria provided, single submitter | not provided |  |
| Athena Diagnostics | benign | criteria provided, single submitter | clinical testing | 2023-12-13 |

## Associated conditions {#conditions}

[coenzyme Q10 deficiency](https://sugi.bio/atlas/disease/coenzyme-q10-deficiency/), [autosomal recessive ataxia due to ubiquinone deficiency](https://sugi.bio/atlas/disease/autosomal-recessive-ataxia-due-to-ubiquinone-deficiency/), [Joubert syndrome 17](https://sugi.bio/atlas/disease/joubert-syndrome-17/).

**Reported phenotype names (ClinVar):** Coenzyme Q10 deficiency, Autosomal recessive ataxia due to ubiquinone deficiency, not specified, not provided, Joubert syndrome 17, Coenzyme Q10 deficiency, primary, AllHighlyPenetrant, none provided, Coenzyme Q10 deficiency, primary, 4, SPINOCEREBELLAR ATAXIA, AUTOSOMAL RECESSIVE 9.

## Similar variants {#similar}

Related COQ8A variant pages (same residue, condition, or type): [COQ8A c.588+1G>C](/variant/coq8a-c-588-plus-1g-c), [COQ8A c.589-3C>G](/variant/coq8a-c-589-minus-3c-g), [COQ8A p.Ala304Val](/variant/coq8a-p-ala304val), [COQ8A p.Ala338Val](/variant/coq8a-p-ala338val), [COQ8A p.Ala339Thr](/variant/coq8a-p-ala339thr), [COQ8A p.Arg160Ter](/variant/coq8a-p-arg160ter), [COQ8A p.Arg213Gln](/variant/coq8a-p-arg213gln), [COQ8A p.Arg213Trp](/variant/coq8a-p-arg213trp).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 2026-10-14); 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 3645). 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.*