Is AFF2 p.Ser969Leu (c.2906C>T) pathogenic?

AFF2 p.Ser969Leu (c.2906C>T) is classified Conflicting classifications of pathogenicity in AFF2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-04-21). AlphaMissense: likely benign (0.0785); Very rare (popmax 0.0022%, amr); Associated with Inborn genetic diseases.

What condition is associated with AFF2 p.Ser969Leu (c.2906C>T)?

AFF2 p.Ser969Leu (c.2906C>T) is associated with Inborn genetic diseases (ClinVar).

How common is AFF2 p.Ser969Leu (c.2906C>T) in the general population?

AFF2 p.Ser969Leu (c.2906C>T) is very rare (popmax 0.0022%, amr) (gnomAD).

What do computational predictors say about AFF2 p.Ser969Leu (c.2906C>T)?

AlphaMissense predicts likely benign (score 0.0785) — an in-silico prediction, not a clinical call.

AFF2 p.Ser969Leu

c.2906C>T · rs782779717 · VCV2661611

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0785 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0785	likely benign
REVEL	0.135	moderately benign-leaning
SaProt	LLR -6.79	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.22 · evaluated, not missing
Constraint at this position
Conservation	phyloP 1.9	GERP 1.9, phastCons 0.93
Regional constraint	o/e 0.94	unconstrained · MANE · 304 kb · p 0.17 · regional, not allelic
Overall
CADD	21.1	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0022% Admixed American · 1/45,541 alleles

Filtering AF 0.00132% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00109%

Overall 0.00164% 19/1,160,768 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0022%	45,541
European (non-Finnish)	0.00211%	47,286

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.Ser969Leu
Coding: c.2906C>T
MANE Select: NM_002025
dbSNP: rs782779717
Type: single nucleotide variant
Location: chrX:148962930 (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.Ser969= Likely benign ★★ 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-ser969leu (accessed [today's date]).

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