Is AFF3 p.Arg590His (c.1769G>A) pathogenic?

AFF3 p.Arg590His (c.1769G>A) is classified Uncertain significance in AFF3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-05). AlphaMissense: ambiguous (0.3705); Very rare (popmax 0.00721%, afr); Associated with Inborn genetic diseases.

What condition is associated with AFF3 p.Arg590His (c.1769G>A)?

AFF3 p.Arg590His (c.1769G>A) is associated with Inborn genetic diseases (ClinVar).

How common is AFF3 p.Arg590His (c.1769G>A) in the general population?

AFF3 p.Arg590His (c.1769G>A) is very rare (popmax 0.00721%, afr) (gnomAD).

What do computational predictors say about AFF3 p.Arg590His (c.1769G>A)?

AlphaMissense predicts ambiguous (score 0.3705) — an in-silico prediction, not a clinical call.

AFF3 p.Arg590His

c.1769G>A · rs769535841 · VCV3092546

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3705 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00721%, afr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3705	ambiguous
REVEL	0.334	indeterminate
SaProt	LLR -8.27	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.7	GERP 2.4, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 16 kb · p 0.083 · regional, not allelic
Overall
CADD	25.7	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 0.00721% African / African-American · 5/69,374 alleles

Filtering AF 0.00281% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00183%

Overall 0.000536% 8/1,492,172 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00721%	13,875
South Asian	0.00132%	75,646
European (non-Finnish)	0.000177%	564,325

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: AFF3
Protein: p.Arg590His
Coding: c.1769G>A
MANE Select: NM_001386135
dbSNP: rs769535841
Type: single nucleotide variant
Location: chr2:99593892 (GRCh38)
Gene constraint: LOEUF 0.318 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 52.20
Residue 590: the 'disordered' region

Full AFF3 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

AFF3 p.Ala233Thr Pathogenic ★★ ⚠ same condition
AFF3 p.Ile1147Asn Uncertain significance ★★ ⚠ same condition
AFF3 p.Leu370Phe Uncertain significance ★★ ⚠ same condition
AFF3 p.Pro321Leu Uncertain significance ★★ ⚠ same condition
AFF3 p.Ser222Thr Uncertain significance ★★ ⚠ same condition
AFF3 p.Thr950Met Uncertain significance ★★ ⚠ same condition
AFF3 p.Ala1100Val Uncertain significance ★ ⚠ same condition
AFF3 p.Ala1103Thr 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/aff3-p-arg590his (accessed [today's date]).

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