Is AFF2 p.Pro520Thr (c.1558C>A) pathogenic?

AFF2 p.Pro520Thr (c.1558C>A) is classified Uncertain significance in AFF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-24). AlphaMissense: ambiguous (0.564); Very rare (popmax 0.00297%, eas).

How common is AFF2 p.Pro520Thr (c.1558C>A) in the general population?

AFF2 p.Pro520Thr (c.1558C>A) is very rare (popmax 0.00297%, eas) (gnomAD).

What do computational predictors say about AFF2 p.Pro520Thr (c.1558C>A)?

AlphaMissense predicts ambiguous (score 0.564) — an in-silico prediction, not a clinical call.

AFF2 p.Pro520Thr

c.1558C>A · rs899028170 · VCV451356

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.564 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00297%, eas)

Computational evidence

Protein change
AlphaMissense	0.564	ambiguous
REVEL	0.54	indeterminate
SaProt	LLR -8.22	tolerated
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	25.3	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 0.00297% East Asian · 1/33,691 alleles

Overall 0.000251% 3/1,194,801 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00297%	33,691
Remaining individualsnot grpmax-eligible	0.00213%	46,922
African / African-American	0.00177%	56,410

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.Pro520Thr
Coding: c.1558C>A
MANE Select: NM_002025
dbSNP: rs899028170
Type: single nucleotide variant
Location: chrX:148955603 (GRCh38)
Structure: AlphaFold pLDDT 49.27
Residue 520: the 'disordered' region

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

Similar variants

AFF2 p.Pro520Ser Uncertain significance ★ ⚠ same residue
AFF2 c.3267+5G>C Uncertain significance ★★ same type
AFF2 p.Ala1197Thr Uncertain significance ★★ ⚠ same type
AFF2 p.Ala171Pro Uncertain significance ★★ ⚠ same type
AFF2 p.Arg1238Cys Uncertain significance ★★ ⚠ same type
AFF2 p.Arg1295Cys Uncertain significance ★★ ⚠ same type
AFF2 p.Arg670His Uncertain significance ★★ ⚠ same type
AFF2 p.Asn77Ile Uncertain significance ★★ ⚠ same type

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-pro520thr (accessed [today's date]).

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