Is AFG2A p.Arg784= (c.2350C>A) pathogenic?

AFG2A p.Arg784= (c.2350C>A) is classified Likely benign in AFG2A (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-06-14). Very rare (popmax 0.000509%, nfe); Associated with microcephaly-intellectual disability-sensorineural hearing loss-epilepsy-abnormal muscle tone syndrome.

How common is AFG2A p.Arg784= (c.2350C>A) in the general population?

AFG2A p.Arg784= (c.2350C>A) is very rare (popmax 0.000509%, nfe) (gnomAD).

AFG2A p.Arg784=

Q: What condition is associated with AFG2A p.Arg784= (c.2350C>A)?

AFG2A p.Arg784= (c.2350C>A) is associated with microcephaly-intellectual disability-sensorineural hearing loss-epilepsy-abnormal muscle tone syndrome (ClinVar).

c.2350C>A · rs978433138 · VCV2143292

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.000509%, 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.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 1.2	GERP -1, phastCons 1
Overall
CADD	8.535	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000509% European (non-Finnish) · 6/1,179,876 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000372% 6/1,613,862 alleles · very rare exomes 6/1,461,680 · genomes 0/152,182 · joint denominator

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.Arg784=
Coding: c.2350C>A
MANE Select: NM_145207
dbSNP: rs978433138
Type: single nucleotide variant
Location: chr4:123256025 (GRCh38)
Structure: AlphaFold pLDDT 73.21 · 2 PDB
Residue 784: a UniProt-annotated variant site (in nedhsb); a UniProt-annotated variant site (in nedhsb; decreased protein stability; no effect on interaction with afg2b and cinp; affects cell viability)

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.Arg784Gln Likely pathogenic ★ 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-arg784 (accessed [today's date]).

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