Is AFF2 p.Trp159Arg (c.475T>C) pathogenic?

AFF2 p.Trp159Arg (c.475T>C) is classified Uncertain significance in AFF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-28). AlphaMissense: likely pathogenic (0.7237); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with AFF2 p.Trp159Arg (c.475T>C)?

AFF2 p.Trp159Arg (c.475T>C) is associated with Inborn genetic diseases (ClinVar).

How common is AFF2 p.Trp159Arg (c.475T>C) in the general population?

AFF2 p.Trp159Arg (c.475T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about AFF2 p.Trp159Arg (c.475T>C)?

AlphaMissense predicts likely pathogenic (score 0.7237) — an in-silico prediction, not a clinical call.

AFF2 p.Trp159Arg

c.475T>C · rs2521396299 · VCV2340563

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7237 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.7237	likely pathogenic
REVEL	0.473	indeterminate
SaProt	LLR -2.84	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 4.2	GERP 2.3, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 161 kb · p 0.93 · regional, not allelic
Overall
CADD	23.6	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: AFF2
Protein: p.Trp159Arg
Coding: c.475T>C
MANE Select: NM_002025
dbSNP: rs2521396299
Type: single nucleotide variant
Location: chrX:148662202 (GRCh38)
Structure: AlphaFold pLDDT 49.27
Residue 159: 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-trp159arg (accessed [today's date]).

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