Is AFG2A p.Arg445Ter (c.1333C>T) pathogenic?

AFG2A p.Arg445Ter (c.1333C>T) is classified Pathogenic/Likely pathogenic in AFG2A (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-11-05). Very rare (popmax 0.00863%, amr); Associated with AFG2A-related disorder.

How common is AFG2A p.Arg445Ter (c.1333C>T) in the general population?

AFG2A p.Arg445Ter (c.1333C>T) is very rare (popmax 0.00863%, amr) (gnomAD).

AFG2A p.Arg445Ter

Q: What condition is associated with AFG2A p.Arg445Ter (c.1333C>T)?

AFG2A p.Arg445Ter (c.1333C>T) is associated with AFG2A-related disorder, microcephaly-intellectual disability-sensorineural hearing loss-epilepsy-abnormal muscle tone syndrome (ClinVar).

c.1333C>T · rs879782394 · VCV948275

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00863%, amr)

Conditions

AFG2A-related disorder

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 7 of 16
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.21 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.29	GERP 0.44, phastCons 0.58
Overall
CADD	37.0	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 0.00863% Admixed American · 5/57,906 alleles

Filtering AF 0.00335% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00213%

Overall 0.000876% 14/1,597,394 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00863%	11,581
East Asian	0.00451%	22,158
Ashkenazi Jewishnot grpmax-eligible	0.00342%	29,242
Remaining individualsnot grpmax-eligible	0.00162%	61,692
European (non-Finnish)	0.000427%	234,418

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.Arg445Ter
Coding: c.1333C>T
MANE Select: NM_145207
dbSNP: rs879782394
Type: single nucleotide variant
Location: chr4:122936155 (GRCh38)
Structure: AlphaFold pLDDT 73.21 · 2 PDB
Residue 445: a UniProt-annotated variant site (in nedhsb)

Full AFG2A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

AFG2A-related disorder

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

Similar variants

AFG2A p.Arg445Gln 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.Arg510Ter Pathogenic/Likely pathogenic ★★ same condition
AFG2A p.Arg514Ter Pathogenic/Likely pathogenic ★★ same condition
AFG2A p.Arg538Ter Pathogenic/Likely pathogenic ★★ same condition
AFG2A p.Arg655Ter 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-arg445ter (accessed [today's date]).

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