Is AFG2A p.Arg655fs (c.1964del) pathogenic?

AFG2A p.Arg655fs (c.1964del) is classified Pathogenic in AFG2A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-26). Very rare (popmax 0.00167%, amr); Associated with microcephaly-intellectual disability-sensorineural hearing loss-epilepsy-abnormal muscle tone syndrome.

How common is AFG2A p.Arg655fs (c.1964del) in the general population?

AFG2A p.Arg655fs (c.1964del) is very rare (popmax 0.00167%, amr) (gnomAD).

AFG2A p.Arg655fs

Q: What condition is associated with AFG2A p.Arg655fs (c.1964del)?

AFG2A p.Arg655fs (c.1964del) is associated with microcephaly-intellectual disability-sensorineural hearing loss-epilepsy-abnormal muscle tone syndrome (ClinVar).

c.1964del · rs1316473569 · VCV951542

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

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 11 of 16
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 2.8	GERP 1.1, phastCons 0.99
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/60,006 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000496% 8/1,614,114 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,006
European (non-Finnish)	0.000593%	168,574

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.Arg655fs
Coding: c.1964del
MANE Select: NM_145207
dbSNP: rs1316473569
Type: Deletion
Location: chr4:123028280 (GRCh38)
Structure: AlphaFold pLDDT 73.21 · 2 PDB
Residue 655: 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.Arg655Ter Pathogenic/Likely pathogenic ★★ same residue
AFG2A p.Arg655Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
AFG2A p.Arg655Gly Uncertain significance ★ ⚠ same residue
AFG2A c.1147+1_1147+5del Likely pathogenic ★★ same condition
AFG2A p.Ala742fs Pathogenic/Likely pathogenic ★★ same condition
AFG2A p.Asn525fs Pathogenic ★★ same condition
AFG2A p.Gly357_Leu358insTer Pathogenic/Likely pathogenic ★★ same condition
AFG2A p.Leu536fs 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-arg655fs (accessed [today's date]).

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