Is AFF3 p.Pro456= (c.1368C>T) pathogenic?

AFF3 p.Pro456= (c.1368C>T) is classified Likely benign in AFF3 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-02-28). Ultra-rare (popmax 0.0832%, mid); Associated with AFF3-related disorder.

What condition is associated with AFF3 p.Pro456= (c.1368C>T)?

AFF3 p.Pro456= (c.1368C>T) is associated with AFF3-related disorder (ClinVar).

How common is AFF3 p.Pro456= (c.1368C>T) in the general population?

AFF3 p.Pro456= (c.1368C>T) is ultra-rare (popmax 0.0832%, mid) (gnomAD).

AFF3 p.Pro456=

c.1368C>T · rs200146886 · VCV3051733

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0832%, mid)

Conditions

AFF3-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -6.2	GERP -4.9
Overall
CADD	3.615	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0832% Middle Eastern · 5/6,012 alleles

Filtering AF 0.0327% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0231%

Overall 0.00368% 59/1,603,810 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0832%	1,202
East Asian	0.0426%	2,347
Admixed American	0.00842%	11,874
Remaining individualsnot grpmax-eligible	0.00484%	20,655
South Asian	0.00447%	22,376
African / African-American	0.004%	24,973
European (non-Finnish)	0.0017%	58,706

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.Pro456=
Coding: c.1368C>T
MANE Select: NM_001386135
dbSNP: rs200146886
Type: single nucleotide variant
Location: chr2:99601438 (GRCh38)
Gene constraint: LOEUF 0.318 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 52.20
Residue 456: 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.Met238Arg Likely pathogenic ★ ⚠ same condition
AFF3 p.His211Asn Uncertain significance ★ ⚠ same condition
AFF3 p.His889Gln Uncertain significance ★ ⚠ same condition
AFF3 p.Lys271Thr Uncertain significance ★ ⚠ same condition
AFF3 p.Pro332Thr Uncertain significance ★ ⚠ same condition
AFF3 p.Ala203Ser Uncertain significance ⚠ same condition
AFF3 c.2591+5G>A Benign same condition
AFF3 c.922-10C>T Benign 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-pro456 (accessed [today's date]).

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