Is AFF2 p.Arg1238Cys (c.3712C>T) pathogenic?

AFF2 p.Arg1238Cys (c.3712C>T) is classified Uncertain significance in AFF2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-10). AlphaMissense: likely pathogenic (0.8884); Very rare (popmax 0.000782%, nfe); Associated with FRAXE intellectual disability.

What condition is associated with AFF2 p.Arg1238Cys (c.3712C>T)?

AFF2 p.Arg1238Cys (c.3712C>T) is associated with FRAXE intellectual disability (ClinVar).

How common is AFF2 p.Arg1238Cys (c.3712C>T) in the general population?

AFF2 p.Arg1238Cys (c.3712C>T) is very rare (popmax 0.000782%, nfe) (gnomAD).

How is FRAXE intellectual disability inherited?

Typically X-linked recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about AFF2 p.Arg1238Cys (c.3712C>T)?

AlphaMissense predicts likely pathogenic (score 0.8884) — an in-silico prediction, not a clinical call.

AFF2 p.Arg1238Cys

c.3712C>T · rs1263514787 · VCV2335186

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8884 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000782%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

FRAXE intellectual disability

Computational evidence

Protein change
AlphaMissense	0.8884	likely pathogenic
REVEL	0.61	indeterminate
SaProt	LLR -11.39	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.8	GERP 1.9, phastCons 1
Regional constraint	o/e 1.13	unconstrained · MANE · 6,718 bp · p 0.42 · regional, not allelic
Overall
CADD	27.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000782% European (non-Finnish) · 7/894,676 alleles

Filtering AF 0.000325% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000209%

Overall 0.000638% 7/1,097,258 alleles · very rare

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.Arg1238Cys
Coding: c.3712C>T
MANE Select: NM_002025
dbSNP: rs1263514787
Type: single nucleotide variant
Location: chrX:148987455 (GRCh38)
Structure: AlphaFold pLDDT 49.27

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

Disease context

FRAXE intellectual disability — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For FRAXE intellectual disability (Orphanet):

Inheritance: X-linked recessive
Onset: Antenatal, Infancy, Neonatal
Prevalence: 1-9 / 1 000 000 (Europe)

Similar variants

AFF2 p.Arg1238= Likely benign ★ same residue
AFF2 c.3267+5G>C Uncertain significance ★★ same condition
AFF2 p.Arg670His Uncertain significance ★★ ⚠ same condition
AFF2 p.Gln391= Uncertain significance ★★ same condition
AFF2 p.Glu489Asp Uncertain significance ★★ ⚠ same condition
AFF2 p.Glu872Gln Uncertain significance ★★ ⚠ same condition
AFF2 p.Leu610Phe Uncertain significance ★★ ⚠ same condition
AFF2 p.Leu614Phe 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-arg1238cys (accessed [today's date]).

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