Is AFG2A p.Gln347fs (c.1039_1040dup) pathogenic?

AFG2A p.Gln347fs (c.10391040dup) is classified Pathogenic in AFG2A (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-09). Very rare (popmax 0.000254%, nfe); Associated with microcephaly-intellectual disability-sensorineural hearing loss-epilepsy-abnormal muscle tone syndrome.

How common is AFG2A p.Gln347fs (c.1039_1040dup) in the general population?

AFG2A p.Gln347fs (c.1039_1040dup) is very rare (popmax 0.000254%, nfe) (gnomAD).

AFG2A p.Gln347fs

Q: What condition is associated with AFG2A p.Gln347fs (c.1039_1040dup)?

AFG2A p.Gln347fs (c.1039_1040dup) is associated with microcephaly-intellectual disability-sensorineural hearing loss-epilepsy-abnormal muscle tone syndrome (ClinVar).

c.1039_1040dup · rs1578528119 · VCV652524

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Conditions

microcephaly-intellectual disability-sensorineural hearing loss-epilepsy-abnormal muscle tone syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 5 of 16
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.51	GERP 0.95

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000254% European (non-Finnish) · 3/1,179,962 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000205% 3/1,461,560 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: AFG2A
Protein: p.Gln347fs
Coding: c.1039_1040dup
MANE Select: NM_145207
dbSNP: rs1578528119
Type: Duplication
Location: chr4:122934629 (GRCh38)
Structure: AlphaFold pLDDT 73.21 · 2 PDB
Residue 347: a UniProt-annotated variant site (in nedhsb)

Full AFG2A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

microcephaly-intellectual disability-sensorineural hearing loss-epilepsy-abnormal muscle tone syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

AFG2A p.Gln347Lys Uncertain significance ★★ ⚠ same residue
AFG2A c.2079+1dup Likely pathogenic ★★ same condition
AFG2A c.164-1053_446+1328dup Likely pathogenic ★ same condition
AFG2A p.Ile155fs Pathogenic ★ same condition
AFG2A p.Lys662Ter Pathogenic ★ same condition
AFG2A c.2505+2dup Uncertain significance ★ same condition
AFG2A c.1870-4dup Benign ★ same condition
AFG2A c.2505+8dup Likely benign ★ 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/afg2a-p-gln347fs (accessed [today's date]).

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