# NM_006796.3(AFG3L2):c.498C>T (p.Ser166=)

https://sugi.bio/variant/afg3l2-p-ser166

## Summary

**AFG3L2 p.Ser166= (c.498C>T)** is classified **Benign** in AFG3L2 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-12-01). Low-frequency (popmax 1.43%, sas); Associated with spinocerebellar ataxia type 28.

**At a glance:** Benign · review: Multiple submitters · rsID rs141538541 · 6 submitters · 1 linked condition · low-frequency (popmax 1.43%, sas)

## For patients & families {#patients}

This is a change in the AFG3L2 gene that is classified as benign — not considered disease-causing, submitted by 6 submitters, and is linked to spinocerebellar ataxia type 28.

*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) | Childhood |
| Clinical trials | 1 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | AFG3L2 is a diagnostic-grade gene on 21 Genomics England panels |

**Commonly reported features of Spinocerebellar ataxia type 28** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Dysarthria — Very frequent (99-80%)
- Gait ataxia — Very frequent (99-80%)
- Limb ataxia — Very frequent (99-80%)
- Lower limb hyperreflexia — Very frequent (99-80%)
- Ptosis — Frequent (79-30%)
- Slow saccadic eye movements — Frequent (79-30%)
- Ophthalmoparesis — Frequent (79-30%)
- Nystagmus — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0009951/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [AFG3L2](https://sugi.bio/atlas/gene/AFG3L2/) |
| Protein change (HGVS p.) | p.Ser166= |
| Coding change (HGVS c.) | c.498C>T |
| MANE Select transcript | [NM_006796](https://www.ncbi.nlm.nih.gov/nuccore/NM_006796) |
| dbSNP | [rs141538541](https://www.ncbi.nlm.nih.gov/snp/rs141538541/) |
| Variant type | single nucleotide variant |
| Location | chr18:12367019-12367019 (GRCh38) |
| ClinVar | [VCV326108](https://www.ncbi.nlm.nih.gov/clinvar/variation/326108/) |

**All HGVS expressions:** `LRG_666:g.15258C>T`, `LRG_666t1:c.498C>T`, `NC_000018.10:g.12367019G>A`, `NC_000018.9:g.12367018G>A`, `NG_023361.1:g.15258C>T`, `NM_006796.3:c.498C>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 -6.267, GERP -3.24 — fast-evolving / accelerated position
- CADD: **PHRED 1.823**. 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 **1.43%** (sas) · FAF95 1.37% · FAF99 1.34% · 1,305/91,072 in the highest group · 1,739/1,614,064 alleles overall — low-frequency (popmax 1.43%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 1.43% | 70 |
| Remaining individuals (not grpmax-eligible) | 0.104% | 962 |
| Middle Eastern | 0.099% | 1,010 |
| European (non-Finnish) | 0.0291% | 3,440 |
| African / African-American | 0.0187% | 5,358 |
| Admixed American | 0.01% | 10,000 |

*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}

**AFG3L2** population constraint: LOEUF 0.724, pLI 1.0227e-08, missense-Z 3.0743. *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):

- **AFG3L2-related optic atrophy and/or spastic ataxia spectrum** — Definitive (SD)

## Protein context {#protein}

Residue **166** lies in a β-strand.

AlphaFold model confidence (whole protein): pLDDT 77.07, 39% of residues very-high.

**2 experimental structure(s)** (PDB): [2LNA](https://www.rcsb.org/structure/2LNA), [6NYY](https://www.rcsb.org/structure/6NYY).

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

*Describes the biological roles of AFG3L2 (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:** AFG3L2's established molecular role includes metalloendopeptidase activity.


### Pathways affected {#pathways}

AFG3L2 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Mitochondrial protein degradation](https://reactome.org/content/detail/R-HSA-9837999) | curated |
| [Processing of SMDT1](https://reactome.org/content/detail/R-HSA-8949664) | curated |

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

**Molecular function:** metalloendopeptidase activity, metallopeptidase activity, ATP hydrolysis activity.

**Biological process:** proteolysis, axonogenesis, protein catabolic process, membrane protein proteolysis, mitochondrial protein processing, calcium import into the mitochondrion.

## Clinical significance {#significance}

**Benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-12-01.

**Submitter consensus:** conflicting (5 Benign, 1 benign).

**Submission history:** 6 submissions (2015–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2015-05-06 |
| Illumina Laboratory Services, Illumina | Benign | criteria provided, single submitter | clinical testing | 2018-01-13 |
| PreventionGenetics, part of Exact Sciences | Benign | no assertion criteria provided | clinical testing | 2019-06-05 |
| Athena Diagnostics | benign | criteria provided, single submitter | clinical testing | 2025-02-13 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2025-10-21 |
| CeGaT Center for Human Genetics Tuebingen | Benign | criteria provided, single submitter | clinical testing | 2025-12-01 |

## Associated conditions {#conditions}

[spinocerebellar ataxia type 28](https://sugi.bio/atlas/disease/spinocerebellar-ataxia-type-28/).

**Reported phenotype names (ClinVar):** Spinocerebellar ataxia type 28, not provided, not specified, AFG3L2-related disorder, AFG3L2-related condition, AllHighlyPenetrant, Spinocerebellar Ataxia Type 28 (SCA28), none provided.

## Similar variants {#similar}

Related AFG3L2 variant pages (same residue, condition, or type): [AFG3L2 p.Gly385Ser](/variant/afg3l2-p-gly385ser), [AFG3L2 p.Gly671Arg](/variant/afg3l2-p-gly671arg), [AFG3L2 p.Met666Thr](/variant/afg3l2-p-met666thr), [AFG3L2 p.Met666Val](/variant/afg3l2-p-met666val), [AFG3L2 p.Thr654Ile](/variant/afg3l2-p-thr654ile), [AFG3L2 p.Tyr689His](/variant/afg3l2-p-tyr689his), [AFG3L2 p.Arg599His](/variant/afg3l2-p-arg599his), [AFG3L2 p.Arg783Trp](/variant/afg3l2-p-arg783trp).

### 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 326108). 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.*