# NM_032340.4(UQCC2):c.102G>A (p.Arg34=)

https://sugi.bio/variant/uqcc2-p-arg34

## Summary

**UQCC2 p.Arg34= (c.102G>A)** is classified **Conflicting classifications of pathogenicity** in UQCC2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-10-20). Ultra-rare (popmax 0.0329%, mid).

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs756874468 · 2 submitters · ultra-rare (popmax 0.0329%, mid)

## For patients & families {#patients}

This is a change in the UQCC2 gene that is of uncertain or conflicting significance (submitters disagree on it), 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 | [UQCC2](https://sugi.bio/atlas/gene/UQCC2/) |
| Protein change (HGVS p.) | p.Arg34= |
| Coding change (HGVS c.) | c.102G>A |
| MANE Select transcript | [NM_032340](https://www.ncbi.nlm.nih.gov/nuccore/NM_032340) |
| dbSNP | [rs756874468](https://www.ncbi.nlm.nih.gov/snp/rs756874468/) |
| Variant type | single nucleotide variant |
| Location | chr6:33711585-33711585 (GRCh38) |
| ClinVar | [VCV2502801](https://www.ncbi.nlm.nih.gov/clinvar/variation/2502801/) |

**All HGVS expressions:** `NC_000006.11:g.33679362C>T`, `NC_000006.12:g.33711585C>T`, `NG_034147.1:g.5167G>A`, `NM_032340.4:c.102G>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 **donor loss** (Δ 0.48) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 4.706, GERP 1.98, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 14.99**. 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 **0.00**, donor loss **0.48**, acceptor gain **0.00**, donor gain **0.01**. Largest is donor loss at this position.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.01**.
  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.*
- Population frequency (gnomAD v4.1): grpmax **0.0329%** (mid) · FAF95 0.00623% · FAF99 0.00467% · 2/6,084 in the highest group · 45/1,613,832 alleles overall — ultra-rare (popmax 0.0329%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.0329% | 3,042 |
| African / African-American | 0.012% | 8,326 |
| Remaining individuals (not grpmax-eligible) | 0.0048% | 20,825 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.00338% | 29,586 |
| European (non-Finnish) | 0.00246% | 40,687 |
| South Asian | 0.0011% | 91,076 |

*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}

**UQCC2** population constraint: LOEUF 1.398, pLI 2.1776e-07, missense-Z 0.9089. *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** — Moderate (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 88.94, 70% of residues very-high.

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

*Describes the biological roles of UQCC2 (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}

UQCC2 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Complex III assembly](https://reactome.org/content/detail/R-HSA-9865881) | electronic |

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

**Biological process:** regulation of oxidative phosphorylation, mitochondrial respiratory chain complex III assembly, positive regulation of mitochondrial translation.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2025-10-20.

**Submitter consensus:** conflicting (1 Uncertain significance, 1 Likely benign).

**Submission history:** 2 submissions (2022–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-11-21 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-10-20 |

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

## Same-residue context {#hotspot}

Residue **34** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [UQCC2 p.Arg34Gln](/variant/uqcc2-p-arg34gln). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related UQCC2 variant pages (same residue, condition, or type): [UQCC2 p.Arg34Gln](/variant/uqcc2-p-arg34gln), [UQCC2 c.214-9G>A](/variant/uqcc2-c-214-minus-9g-a), [UQCC2 c.283+3A>C](/variant/uqcc2-c-283-plus-3a-c), [UQCC2 p.Ala2Thr](/variant/uqcc2-p-ala2thr), [UQCC2 p.Ala38Thr](/variant/uqcc2-p-ala38thr), [UQCC2 p.Ala61Val](/variant/uqcc2-p-ala61val), [UQCC2 p.Gln46=](/variant/uqcc2-p-gln46), [UQCC2 p.Thr21Pro](/variant/uqcc2-p-thr21pro).

### 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 2502801). 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.*