Is AFF2 p.Arg599Trp (c.1795C>T) pathogenic?

AFF2 p.Arg599Trp (c.1795C>T) is classified Likely benign in AFF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-12-13). AlphaMissense: ambiguous (0.3561); Very rare (popmax 0.00827%, nfe); Associated with Inborn genetic diseases.

What condition is associated with AFF2 p.Arg599Trp (c.1795C>T)?

AFF2 p.Arg599Trp (c.1795C>T) is associated with Inborn genetic diseases (ClinVar).

How common is AFF2 p.Arg599Trp (c.1795C>T) in the general population?

AFF2 p.Arg599Trp (c.1795C>T) is very rare (popmax 0.00827%, nfe) (gnomAD).

What do computational predictors say about AFF2 p.Arg599Trp (c.1795C>T)?

AlphaMissense predicts ambiguous (score 0.3561) — an in-silico prediction, not a clinical call.

AFF2 p.Arg599Trp

c.1795C>T · rs373295539 · VCV2407833

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3561 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00827%, nfe)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3561	ambiguous
REVEL	0.476	indeterminate
SaProt	LLR -9.27	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.86	GERP 1.6, phastCons 0.23
Regional constraint	o/e 0.94	unconstrained · MANE · 304 kb · p 0.17 · regional, not allelic
Overall
CADD	23.9	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 0.00827% European (non-Finnish) · 74/895,208 alleles

Filtering AF 0.00673% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00617%

Overall 0.00645% 78/1,209,627 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00827%	12,097
South Asian	0.00705%	14,186

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.Arg599Trp
Coding: c.1795C>T
MANE Select: NM_002025
dbSNP: rs373295539
Type: single nucleotide variant
Location: chrX:148955840 (GRCh38)
Structure: AlphaFold pLDDT 49.27
Residue 599: 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-arg599trp (accessed [today's date]).

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