Is AFG2B p.Ala559fs (c.1676del) pathogenic?

AFG2B p.Ala559fs (c.1676del) is classified Likely pathogenic in AFG2B (ClinVar, No assertion criteria, 1 submitter). Very rare (popmax 8.47e-05%, nfe).

How common is AFG2B p.Ala559fs (c.1676del) in the general population?

AFG2B p.Ala559fs (c.1676del) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

AFG2B p.Ala559fs

c.1676del · rs767220705 · VCV1210110

Likely pathogenic No assertion criteria

Classification

Likely pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

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 5 of 8
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,179,978 alleles

Overall 0.000205% 3/1,461,796 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,492
Finnishnot grpmax-eligible	0.00156%	63,980
European (non-Finnish)grpmax	8.47e-05%	1,179,979

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: AFG2B
Protein: p.Ala559fs
Coding: c.1676del
MANE Select: NM_024063
dbSNP: rs767220705
Type: Deletion
Location: chr15:45415618 (GRCh38)
Structure: AlphaFold pLDDT 77.37 · 2 PDB

Full AFG2B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

AFG2B p.Ile435fs Pathogenic ★ same type
AFG2B p.Val726fs Pathogenic ★ same type
AFG2B p.Phe687del Uncertain significance ★ same type
AFG2B p.Gln716fs Pathogenic same type

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/afg2b-p-ala559fs (accessed [today's date]).

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