Is AFG2A p.Ile418fs (c.1254_1257del) pathogenic?

AFG2A p.Ile418fs (c.12541257del) is classified Pathogenic in AFG2A (ClinVar, Single submitter, 1 submitter; last evaluated 2022-02-20). Absent from gnomAD; Associated with microcephaly-intellectual disability-sensorineural hearing loss-epilepsy-abnormal muscle tone syndrome.

How common is AFG2A p.Ile418fs (c.1254_1257del) in the general population?

AFG2A p.Ile418fs (c.1254_1257del) is absent from gnomAD (gnomAD).

AFG2A p.Ile418fs

Q: What condition is associated with AFG2A p.Ile418fs (c.1254_1257del)?

AFG2A p.Ile418fs (c.1254_1257del) is associated with microcephaly-intellectual disability-sensorineural hearing loss-epilepsy-abnormal muscle tone syndrome (ClinVar).

c.1254_1257del · rs2476819449 · VCV2100148

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Not reported

no gnomAD frequency available for this variant

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 6 of 16
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 5	GERP -0.24, phastCons 1

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

Population frequency

dbSNP / gnomAD

No gnomAD frequency available for this variant. This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: AFG2A
Protein: p.Ile418fs
Coding: c.1254_1257del
MANE Select: NM_145207
dbSNP: rs2476819449
Type: Microsatellite
Location: chr4:122935816 (GRCh38)
Structure: AlphaFold pLDDT 73.21 · 2 PDB
Residue 418: 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.Ile418Thr Uncertain significance ★ ⚠ same residue
AFG2A p.Thr330del Pathogenic/Likely pathogenic ★★ same condition
AFG2A p.Lys5del Uncertain significance ★ same condition
AFG2A p.Ter894ArgextTer? Uncertain significance ★ same condition
AFG2A c.447-15_447-13del Likely benign ★ same condition
AFG2A p.Glu711fs Pathogenic same condition
AFG2A c.1147+1_1147+5del Likely pathogenic ★★ same condition
AFG2A c.1714+1G>A 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/afg2a-p-ile418fs (accessed [today's date]).

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