Is AFF2 p.Pro522Ser (c.1564C>T) pathogenic?

AFF2 p.Pro522Ser (c.1564C>T) is classified Uncertain significance in AFF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-04). AlphaMissense: likely pathogenic (0.577); Very rare (popmax 0.00175%, afr); Associated with Inborn genetic diseases.

What condition is associated with AFF2 p.Pro522Ser (c.1564C>T)?

AFF2 p.Pro522Ser (c.1564C>T) is associated with Inborn genetic diseases (ClinVar).

How common is AFF2 p.Pro522Ser (c.1564C>T) in the general population?

AFF2 p.Pro522Ser (c.1564C>T) is very rare (popmax 0.00175%, afr) (gnomAD).

What do computational predictors say about AFF2 p.Pro522Ser (c.1564C>T)?

AlphaMissense predicts likely pathogenic (score 0.577) — an in-silico prediction, not a clinical call.

AFF2 p.Pro522Ser

c.1564C>T · rs2521890013 · VCV3092380

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.577 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00175%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.577	likely pathogenic
REVEL	0.508	indeterminate
SaProt	LLR -7.30	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.8, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 304 kb · p 0.17 · regional, not allelic
Overall
CADD	25.2	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 0.00175% African / African-American · 1/57,131 alleles

Filtering AF 0.000387% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000279%

Overall 0.000829% 9/1,085,117 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00175%	57,131
European (non-Finnish)	0.000899%	111,268

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.Pro522Ser
Coding: c.1564C>T
MANE Select: NM_002025
dbSNP: rs2521890013
Type: single nucleotide variant
Location: chrX:148955609 (GRCh38)
Structure: AlphaFold pLDDT 49.27
Residue 522: the 'disordered' region

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.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
AFF2 p.His366Arg 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-pro522ser (accessed [today's date]).

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