Is AFG2A p.Asp588Ter (c.1761dup) pathogenic?

AFG2A p.Asp588Ter (c.1761dup) is classified Likely pathogenic in AFG2A (ClinVar, No assertion criteria, 1 submitter). Absent from gnomAD; Associated with microcephaly-intellectual disability-sensorineural hearing loss-epilepsy-abnormal muscle tone syndrome.

How common is AFG2A p.Asp588Ter (c.1761dup) in the general population?

AFG2A p.Asp588Ter (c.1761dup) is absent from gnomAD (gnomAD).

AFG2A p.Asp588Ter

Q: What condition is associated with AFG2A p.Asp588Ter (c.1761dup)?

AFG2A p.Asp588Ter (c.1761dup) is associated with microcephaly-intellectual disability-sensorineural hearing loss-epilepsy-abnormal muscle tone syndrome (ClinVar).

c.1761dup · rs2477396580 · VCV2443984

Likely pathogenic No assertion criteria

Classification

Likely pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

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	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 10 of 16
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.4	GERP 1.5, 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.Asp588Ter
Coding: c.1761dup
MANE Select: NM_145207
dbSNP: rs2477396580
Type: Duplication
Location: chr4:122979277 (GRCh38)
Structure: AlphaFold pLDDT 73.21 · 2 PDB
Residue 588: 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.Asp588fs Pathogenic ★ same residue
AFG2A c.2079+1dup Likely pathogenic ★★ same condition
AFG2A c.164-1053_446+1328dup Likely pathogenic ★ same condition
AFG2A p.Gln347fs 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

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-asp588ter (accessed [today's date]).

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