Is AFG2A p.Glu684Asp (c.2052G>C) pathogenic?

AFG2A p.Glu684Asp (c.2052G>C) is classified Uncertain significance in AFG2A (ClinVar, Single submitter, 1 submitter; last evaluated 2020-06-03). AlphaMissense: ambiguous (0.5192); Absent from gnomAD v4.1; Associated with microcephaly-intellectual disability-sensorineural hearing loss-epilepsy-abnormal muscle tone syndrome.

How common is AFG2A p.Glu684Asp (c.2052G>C) in the general population?

AFG2A p.Glu684Asp (c.2052G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about AFG2A p.Glu684Asp (c.2052G>C)?

AlphaMissense predicts ambiguous (score 0.5192) — an in-silico prediction, not a clinical call.

AFG2A p.Glu684Asp

Q: What condition is associated with AFG2A p.Glu684Asp (c.2052G>C)?

AFG2A p.Glu684Asp (c.2052G>C) is associated with microcephaly-intellectual disability-sensorineural hearing loss-epilepsy-abnormal muscle tone syndrome (ClinVar).

c.2052G>C · rs1473246053 · VCV1040949

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5192 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

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

Computational evidence

Protein change
AlphaMissense	0.5192	ambiguous
REVEL	0.729	pathogenic-leaning
SaProt	LLR -10.67	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.6	GERP -2.2, phastCons 1
Regional constraint	o/e 0.67	unconstrained · MANE · 62 kb · p 7.1e-05 · regional, not allelic
Overall
CADD	21.8	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: AFG2A
Protein: p.Glu684Asp
Coding: c.2052G>C
MANE Select: NM_145207
dbSNP: rs1473246053
Type: single nucleotide variant
Location: chr4:123028368 (GRCh38)
Structure: AlphaFold pLDDT 73.21 · 2 PDB
Residue 684: 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.Glu684Lys Uncertain significance ★★ ⚠ same residue
AFG2A c.1714+1G>A Pathogenic ★★ same condition
AFG2A c.446+1G>A Likely pathogenic ★★ same condition
AFG2A p.Ala844Val Pathogenic/Likely pathogenic ★★ ⚠ same condition
AFG2A p.Arg445Ter Pathogenic/Likely pathogenic ★★ same condition
AFG2A p.Arg510Ter Pathogenic/Likely pathogenic ★★ same condition
AFG2A p.Arg514Ter Pathogenic/Likely pathogenic ★★ same condition
AFG2A p.Arg538Ter Pathogenic/Likely 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-glu684asp (accessed [today's date]).

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