Is AFG3L2 p.Thr355= (c.1065G>A) pathogenic?

AFG3L2 p.Thr355= (c.1065G>A) is classified Benign/Likely benign in AFG3L2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-11-01). Ultra-rare (popmax 0.0247%, nfe); Associated with spinocerebellar ataxia type 28.

What condition is associated with AFG3L2 p.Thr355= (c.1065G>A)?

AFG3L2 p.Thr355= (c.1065G>A) is associated with spinocerebellar ataxia type 28 (ClinVar).

How common is AFG3L2 p.Thr355= (c.1065G>A) in the general population?

AFG3L2 p.Thr355= (c.1065G>A) is ultra-rare (popmax 0.0247%, nfe) (gnomAD).

How is Spinocerebellar ataxia type 28 inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

AFG3L2 p.Thr355=

c.1065G>A · rs139181972 · VCV668162

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0247%, nfe)

Conditions

spinocerebellar ataxia type 28

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -6.5	GERP -3.9
Overall
CADD	1.306	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0247% European (non-Finnish) · 292/1,180,042 alleles

Filtering AF 0.0224% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0215%

Overall 0.0188% 304/1,614,060 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0247%	4,041
Remaining individualsnot grpmax-eligible	0.0144%	6,943
African / African-American	0.00267%	37,468
Finnishnot grpmax-eligible	0.00156%	64,032

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: AFG3L2
Protein: p.Thr355=
Coding: c.1065G>A
MANE Select: NM_006796
dbSNP: rs139181972
Type: single nucleotide variant
Location: chr18:12356793 (GRCh38)
Gene constraint: LOEUF 0.724 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.07 · 2 PDB
Residue 355: a binding site

Full AFG3L2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

spinocerebellar ataxia type 28 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Spinocerebellar ataxia type 28 (Orphanet):

Inheritance: Autosomal dominant
Onset: Childhood

Similar variants

AFG3L2 p.Thr355Met Conflicting classifications of pathogenicity ★ ⚠ same residue
AFG3L2 p.Gly385Ser Likely pathogenic ★★ same condition
AFG3L2 p.Gly671Arg Pathogenic ★★ same condition
AFG3L2 p.Met666Thr Pathogenic/Likely pathogenic ★★ same condition
AFG3L2 p.Met666Val Pathogenic/Likely pathogenic ★★ same condition
AFG3L2 p.Thr654Ile Likely pathogenic ★★ same condition
AFG3L2 p.Tyr689His Pathogenic/Likely pathogenic ★★ same condition
AFG3L2 p.Arg599His Uncertain significance ★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/afg3l2-p-thr355 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown