Is AFG3L2 p.Pro30Leu (c.89C>T) pathogenic?

AFG3L2 p.Pro30Leu (c.89C>T) is classified Uncertain significance in AFG3L2 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-13). AlphaMissense: likely benign (0.0747); Very rare (popmax 0.0024%, amr); Associated with spinocerebellar ataxia type 28.

What condition is associated with AFG3L2 p.Pro30Leu (c.89C>T)?

AFG3L2 p.Pro30Leu (c.89C>T) is associated with spinocerebellar ataxia type 28 (ClinVar).

How common is AFG3L2 p.Pro30Leu (c.89C>T) in the general population?

AFG3L2 p.Pro30Leu (c.89C>T) is very rare (popmax 0.0024%, amr) (gnomAD).

How is Spinocerebellar ataxia type 28 inherited?

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

What do computational predictors say about AFG3L2 p.Pro30Leu (c.89C>T)?

AlphaMissense predicts likely benign (score 0.0747) — an in-silico prediction, not a clinical call.

AFG3L2 p.Pro30Leu

c.89C>T · rs886053617 · VCV326115

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0747 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0024%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

spinocerebellar ataxia type 28

Computational evidence

Protein change
AlphaMissense	0.0747	likely benign
REVEL	0.229	benign-leaning
SaProt	LLR -6.13	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.8	GERP -2, phastCons 0.013
Regional constraint	o/e 1.10	unconstrained · MANE · 10 kb · p 0.13 · regional, not allelic
Overall
CADD	6.764	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0024% Admixed American · 1/41,676 alleles

Overall 0.000229% 3/1,308,474 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0038%	26,330
Admixed Americangrpmax	0.0024%	41,676
European (non-Finnish)	9e-05%	1,110,671

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. 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.

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.Pro30Leu
Coding: c.89C>T
MANE Select: NM_006796
dbSNP: rs886053617
Type: single nucleotide variant
Location: chr18:12376994 (GRCh38)
Gene constraint: LOEUF 0.724 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.07 · 2 PDB

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.Pro30Ser Uncertain significance ★★ ⚠ same residue
AFG3L2 p.Pro30Thr Uncertain significance ★ ⚠ 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

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-pro30leu (accessed [today's date]).

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