Is AFF3 p.Thr594fs (c.1781_1785del) pathogenic?

AFF3 p.Thr594fs (c.17811785del) is classified Benign in AFF3 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-03-25). Common (popmax 18.2%, eas) — too common for a highly-penetrant pathogenic allele; Associated with AFF3-related disorder.

What condition is associated with AFF3 p.Thr594fs (c.1781_1785del)?

AFF3 p.Thr594fs (c.1781_1785del) is associated with AFF3-related disorder (ClinVar).

AFF3 p.Thr594fs

Q: How common is AFF3 p.Thr594fs (c.1781_1785del) in the general population?

AFF3 p.Thr594fs (c.1781_1785del) is common (popmax 18.2%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1781_1785del · rs199557232 · VCV3059258

Benign No assertion criteria

Classification

Benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Common

common (popmax 18.2%, eas) — too common for a highly-penetrant pathogenic allele

Conditions

AFF3-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a LoF-intolerant gene
NMD	predicted	premature termination codon in exon 15 of 25
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 2.1	GERP 1.4, phastCons 0.97
Overall
CADD	29.6	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 18.2% East Asian · 7,841/43,120 alleles

Filtering AF 17.8% ClinGen BA1/BS1 input FAF95, joint · FAF99 17.7%

Overall 5.43% 84,173/1,550,462 alleles · common

Ancestry group	Frequency	1 in
East Asiangrpmax	18.2%	5
Middle Eastern	6.47%	15
Remaining individualsnot grpmax-eligible	6.13%	16
European (non-Finnish)	5.41%	18
South Asian	4.93%	20
Admixed American	4.45%	22
Ashkenazi Jewishnot grpmax-eligible	3.7%	27
Finnishnot grpmax-eligible	3.02%	33
African / African-American	1.21%	82
Amishnot grpmax-eligible	0.11%	912

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: AFF3
Protein: p.Thr594fs
Coding: c.1781_1785del
MANE Select: NM_001386135
dbSNP: rs199557232
Type: Deletion
Location: chr2:99593876 (GRCh38)
Gene constraint: LOEUF 0.318 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 52.20
Residue 594: the 'disordered' region

Full AFF3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

AFF3-related disorder

Similar variants

AFF3 p.Glu606fs Uncertain significance ★ same condition
AFF3 p.Thr594_Ala596delinsSer Conflicting classifications of pathogenicity ★ same residue
AFF3 p.Thr594Ser Likely benign ★ same residue
AFF3 p.Met238Arg Likely pathogenic ★ ⚠ same condition
AFF3 p.Pro231Arg Pathogenic ★ same condition
AFF3 p.Asn937del Uncertain significance ★ same condition
AFF3 p.His211Asn Uncertain significance ★ ⚠ same condition
AFF3 p.His889Gln Uncertain significance ★ ⚠ 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/aff3-p-thr594fs (accessed [today's date]).

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