Is AFF2 p.Ser969= (c.2907G>A) pathogenic?

AFF2 p.Ser969= (c.2907G>A) is classified Likely benign in AFF2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2023-11-13). Ultra-rare (popmax 0.0268%, afr); Associated with Inborn genetic diseases.

What condition is associated with AFF2 p.Ser969= (c.2907G>A)?

AFF2 p.Ser969= (c.2907G>A) is associated with Inborn genetic diseases (ClinVar).

How common is AFF2 p.Ser969= (c.2907G>A) in the general population?

AFF2 p.Ser969= (c.2907G>A) is ultra-rare (popmax 0.0268%, afr) (gnomAD).

AFF2 p.Ser969=

c.2907G>A · rs781838895 · VCV742055

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0268%, afr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.65	donor loss · deltas
Constraint at this position
Conservation	phyloP -2.7	GERP -3.9
Overall
CADD	5.339	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0268% African / African-American · 15/56,066 alleles

Filtering AF 0.0164% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0133%

Overall 0.00345% 40/1,160,922 alleles · ultra-rare exomes 27/1,049,510 · genomes 13/111,412 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0268%	3,738
East Asian	0.00596%	16,776
Admixed American	0.00439%	22,777
European (non-Finnish)	0.00223%	44,800
Remaining individualsnot grpmax-eligible	0.00217%	46,005
South Asian	0.0018%	55,474

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: AFF2
Protein: p.Ser969=
Coding: c.2907G>A
MANE Select: NM_002025
dbSNP: rs781838895
Type: single nucleotide variant
Location: chrX:148962931 (GRCh38)
Structure: AlphaFold pLDDT 49.27

Full AFF2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

AFF2 p.Ser969Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
AFF2 p.Ala1197Thr Uncertain significance ★★ ⚠ same condition
AFF2 p.Arg1295Cys Uncertain significance ★★ ⚠ same condition
AFF2 p.Asp187Glu Uncertain significance ★★ ⚠ same condition
AFF2 p.Gln205Lys Uncertain significance ★★ ⚠ same condition
AFF2 p.Gly482Arg Uncertain significance ★★ ⚠ same condition
AFF2 p.Gly740Val Uncertain significance ★★ ⚠ same condition
AFF2 p.His1070Arg 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/aff2-p-ser969 (accessed [today's date]).

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