Is AFF2 p.Arg22Cys (c.64C>T) pathogenic?

AFF2 p.Arg22Cys (c.64C>T) is classified Uncertain significance in AFF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2016-03-31). AlphaMissense: likely pathogenic (0.8746); Very rare (popmax 0.00666%, amr).

How common is AFF2 p.Arg22Cys (c.64C>T) in the general population?

AFF2 p.Arg22Cys (c.64C>T) is very rare (popmax 0.00666%, amr) (gnomAD).

What do computational predictors say about AFF2 p.Arg22Cys (c.64C>T)?

AlphaMissense predicts likely pathogenic (score 0.8746) — an in-silico prediction, not a clinical call.

AFF2 p.Arg22Cys

c.64C>T · rs372514798 · VCV286419

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8746 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00666%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8746	likely pathogenic
REVEL	0.814	moderately pathogenic-leaning
SaProt	LLR -6.91	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 3.2	GERP 2.7, 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

Grpmax group 0.00666% Admixed American · 3/45,048 alleles

Filtering AF 0.00177% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00089%

Overall 0.00108% 13/1,198,868 alleles · very rare exomes 12/1,088,277 · genomes 1/110,591 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00666%	15,016
Remaining individualsnot grpmax-eligible	0.00212%	47,174
African / African-American	0.00177%	56,495
European (non-Finnish)	0.0009%	111,059

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.Arg22Cys
Coding: c.64C>T
MANE Select: NM_002025
dbSNP: rs372514798
Type: single nucleotide variant
Location: chrX:148652015 (GRCh38)
Structure: AlphaFold pLDDT 49.27

Full AFF2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

AFF2 c.3267+5G>C Uncertain significance ★★ same type
AFF2 p.Ala1197Thr Uncertain significance ★★ ⚠ same type
AFF2 p.Ala171Pro Uncertain significance ★★ ⚠ same type
AFF2 p.Arg1238Cys Uncertain significance ★★ ⚠ same type
AFF2 p.Arg1295Cys Uncertain significance ★★ ⚠ same type
AFF2 p.Arg670His Uncertain significance ★★ ⚠ same type
AFF2 p.Asn77Ile Uncertain significance ★★ ⚠ same type
AFF2 p.Asp187Glu Uncertain significance ★★ ⚠ same type

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-arg22cys (accessed [today's date]).

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