Is AFG3L2 p.Arg397Gln (c.1190G>A) pathogenic?

AFG3L2 p.Arg397Gln (c.1190G>A) is classified Uncertain significance in AFG3L2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-11). AlphaMissense: likely pathogenic (0.7191); Very rare (popmax 0.00446%, eas).

How common is AFG3L2 p.Arg397Gln (c.1190G>A) in the general population?

AFG3L2 p.Arg397Gln (c.1190G>A) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about AFG3L2 p.Arg397Gln (c.1190G>A)?

AlphaMissense predicts likely pathogenic (score 0.7191) — an in-silico prediction, not a clinical call.

AFG3L2 p.Arg397Gln

c.1190G>A · VCV4705564

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7191 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7191	likely pathogenic
REVEL	0.799	moderately pathogenic-leaning
SaProt	LLR -9.25	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 0.75, phastCons 1
Regional constraint	o/e 0.48	unconstrained · MANE · 7,589 bp · p 4.6e-15 · regional, not allelic
Overall
CADD	29.4	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00446% East Asian · 2/44,882 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000276%

Overall 0.000821% 12/1,461,826 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,441
Admixed American	0.00167%	59,998
Remaining individualsnot grpmax-eligible	0.0016%	62,498
South Asian	0.0011%	91,080
European (non-Finnish)	0.000593%	168,566

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.Arg397Gln
Coding: c.1190G>A
MANE Select: NM_006796
Type: single nucleotide variant
Location: chr18:12353133 (GRCh38)
Gene constraint: LOEUF 0.724 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.07 · 2 PDB
Residue 397: an α-helix

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

Similar variants

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AFG3L2 p.Gly337Glu Pathogenic ★★ same type
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AFG3L2 p.Gly671Arg Pathogenic ★★ same type
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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-arg397gln (accessed [today's date]).

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