Is AFF2 p.Val289Ile (c.865G>A) pathogenic?

AFF2 p.Val289Ile (c.865G>A) is classified Uncertain significance in AFF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-15). AlphaMissense: ambiguous (0.3437); Very rare (popmax 0.00174%, afr); Associated with Inborn genetic diseases.

What condition is associated with AFF2 p.Val289Ile (c.865G>A)?

AFF2 p.Val289Ile (c.865G>A) is associated with Inborn genetic diseases (ClinVar).

How common is AFF2 p.Val289Ile (c.865G>A) in the general population?

AFF2 p.Val289Ile (c.865G>A) is very rare (popmax 0.00174%, afr) (gnomAD).

What do computational predictors say about AFF2 p.Val289Ile (c.865G>A)?

AlphaMissense predicts ambiguous (score 0.3437) — an in-silico prediction, not a clinical call.

AFF2 p.Val289Ile

c.865G>A · VCV3274509

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3437 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00174%, afr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3437	ambiguous
REVEL	0.518	indeterminate
SaProt	LLR -6.47	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 2.8, phastCons 1
Regional constraint	o/e 0.20	constrained · MANE · 72 bp · p 0.00039 · regional, not allelic
Overall
CADD	23.5	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 0.00174% African / African-American · 1/57,624 alleles

Filtering AF 0.000241% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000158%

Overall 0.000637% 7/1,098,216 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00174%	57,624
European (non-Finnish)	0.00067%	149,242

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.Val289Ile
Coding: c.865G>A
MANE Select: NM_002025
Type: single nucleotide variant
Location: chrX:148662592 (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.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-val289ile (accessed [today's date]).

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