Is AFF2 p.Arg161Ser (c.481C>A) pathogenic?

AFF2 p.Arg161Ser (c.481C>A) is classified Conflicting classifications of pathogenicity in AFF2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-04-12). AlphaMissense: ambiguous (0.3657); Ultra-rare (popmax 0.0131%, amr); Associated with Inborn genetic diseases.

What condition is associated with AFF2 p.Arg161Ser (c.481C>A)?

AFF2 p.Arg161Ser (c.481C>A) is associated with Inborn genetic diseases (ClinVar).

How common is AFF2 p.Arg161Ser (c.481C>A) in the general population?

AFF2 p.Arg161Ser (c.481C>A) is ultra-rare (popmax 0.0131%, amr) (gnomAD).

What do computational predictors say about AFF2 p.Arg161Ser (c.481C>A)?

AlphaMissense predicts ambiguous (score 0.3657) — an in-silico prediction, not a clinical call.

AFF2 p.Arg161Ser

c.481C>A · rs782411248 · VCV382520

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3657 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0131%, amr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3657	ambiguous
REVEL	0.267	benign-leaning
SaProt	LLR -5.33	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1	GERP 1.4, phastCons 0.82
Regional constraint	o/e 1.01	unconstrained · MANE · 161 kb · p 0.93 · regional, not allelic
Overall
CADD	22.4	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 0.0131% Admixed American · 6/45,701 alleles

Filtering AF 0.0057% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00388%

Overall 0.000745% 9/1,208,782 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0131%	7,617
African / African-American	0.00175%	57,058
European (non-Finnish)	0.000224%	447,169

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.Arg161Ser
Coding: c.481C>A
MANE Select: NM_002025
dbSNP: rs782411248
Type: single nucleotide variant
Location: chrX:148662208 (GRCh38)
Structure: AlphaFold pLDDT 49.27
Residue 161: 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.Arg161His Uncertain significance ★ ⚠ same residue
AFF2 p.Arg161Cys Likely benign ★ ⚠ same residue
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

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-arg161ser (accessed [today's date]).

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