Is AFG2A p.Ser18= (c.54G>C) pathogenic?

AFG2A p.Ser18= (c.54G>C) is classified Likely benign in AFG2A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-06). Absent from gnomAD v4.1; Associated with microcephaly-intellectual disability-sensorineural hearing loss-epilepsy-abnormal muscle tone syndrome.

How common is AFG2A p.Ser18= (c.54G>C) in the general population?

AFG2A p.Ser18= (c.54G>C) is absent from gnomAD v4.1 (gnomAD).

AFG2A p.Ser18=

Q: What condition is associated with AFG2A p.Ser18= (c.54G>C)?

AFG2A p.Ser18= (c.54G>C) is associated with microcephaly-intellectual disability-sensorineural hearing loss-epilepsy-abnormal muscle tone syndrome (ClinVar).

c.54G>C · rs2125713813 · VCV1532132

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Absent

absent from gnomAD v4.1

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/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.23	donor loss, 5 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP -0.23	GERP -1.1
Overall
CADD	6.365	PHRED · no single calibrated threshold — expert panels disagree

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.Ser18=
Coding: c.54G>C
MANE Select: NM_145207
dbSNP: rs2125713813
Type: single nucleotide variant
Location: chr4:122923196 (GRCh38)
Structure: AlphaFold pLDDT 73.21 · 2 PDB
Residue 18: the 'required for interaction with afg2b and cinp' region; the 'disordered' region

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.Ser18Trp 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-ser18 (accessed [today's date]).

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