Is AFF2 p.Arg670His (c.2009G>A) pathogenic?

AFF2 p.Arg670His (c.2009G>A) is classified Uncertain significance in AFF2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2020-04-24). AlphaMissense: likely benign (0.1991); Very rare (popmax 0.00353%, sas); Associated with FRAXE intellectual disability.

What condition is associated with AFF2 p.Arg670His (c.2009G>A)?

AFF2 p.Arg670His (c.2009G>A) is associated with FRAXE intellectual disability (ClinVar).

How common is AFF2 p.Arg670His (c.2009G>A) in the general population?

AFF2 p.Arg670His (c.2009G>A) is very rare (popmax 0.00353%, sas) (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.Arg670His (c.2009G>A)?

AlphaMissense predicts likely benign (score 0.1991) — an in-silico prediction, not a clinical call.

AFF2 p.Arg670His

c.2009G>A · rs1569557647 · VCV624447

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1991 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00353%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

FRAXE intellectual disability

Computational evidence

Protein change
AlphaMissense	0.1991	likely benign
REVEL	0.234	benign-leaning
SaProt	LLR -7.71	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.4	GERP 1.6, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 304 kb · p 0.17 · regional, not allelic
Overall
CADD	25.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00353% South Asian · 2/56,586 alleles

Filtering AF 0.000586% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000343%

Overall 0.00091% 11/1,208,481 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00353%	28,293
European (non-Finnish)	0.00101%	99,431

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.Arg670His
Coding: c.2009G>A
MANE Select: NM_002025
dbSNP: rs1569557647
Type: single nucleotide variant
Location: chrX:148956054 (GRCh38)
Structure: AlphaFold pLDDT 49.27
Residue 670: the 'disordered' region

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.Arg670Leu Uncertain significance ★ same residue
AFF2 c.3267+5G>C Uncertain significance ★★ same condition
AFF2 p.Arg1238Cys 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-arg670his (accessed [today's date]).

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