Is AFG3L2 p.Met1Ile (c.3G>A) pathogenic?

AFG3L2 p.Met1Ile (c.3G>A) is classified Uncertain significance in AFG3L2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-02). Very rare (popmax 0.000552%, nfe).

How common is AFG3L2 p.Met1Ile (c.3G>A) in the general population?

AFG3L2 p.Met1Ile (c.3G>A) is very rare (popmax 0.000552%, nfe) (gnomAD).

AFG3L2 p.Met1Ile

c.3G>A · VCV3694271

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

start-loss

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000552%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	start-loss	predicted loss-of-function
REVEL	0.605	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.8	GERP 1, phastCons 1
Overall
CADD	22.6	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000552% European (non-Finnish) · 6/1,086,006 alleles

Filtering AF 0.000199% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000131%

Overall 0.000423% 6/1,418,360 alleles · very rare

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.Met1Ile
Coding: c.3G>A
MANE Select: NM_006796
Type: single nucleotide variant
Location: chr18:12377080 (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

Similar variants

AFG3L2 p.Arg41Ter Pathogenic/Likely pathogenic ★★ same type
AFG3L2 p.Arg468Cys Pathogenic/Likely pathogenic ★★ same type
AFG3L2 p.Arg68Ter Pathogenic ★★ same type
AFG3L2 p.Gly337Glu Pathogenic ★★ same type
AFG3L2 p.Gly385Ser Likely pathogenic ★★ same type
AFG3L2 p.Gly671Arg Pathogenic ★★ same type
AFG3L2 p.Met666Thr Pathogenic/Likely pathogenic ★★ same type
AFG3L2 p.Met666Val Pathogenic/Likely pathogenic ★★ same type

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-met1ile (accessed [today's date]).

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