Is AFF2 p.Arg853His (c.2558G>A) pathogenic?

AFF2 p.Arg853His (c.2558G>A) is classified Uncertain significance in AFF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-01-01). AlphaMissense: ambiguous (0.5308); Very rare (popmax 0.00889%, eas); Associated with FRAXE intellectual disability.

What condition is associated with AFF2 p.Arg853His (c.2558G>A)?

AFF2 p.Arg853His (c.2558G>A) is associated with FRAXE intellectual disability (ClinVar).

How common is AFF2 p.Arg853His (c.2558G>A) in the general population?

AFF2 p.Arg853His (c.2558G>A) is very rare (popmax 0.00889%, eas) (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.Arg853His (c.2558G>A)?

AlphaMissense predicts ambiguous (score 0.5308) — an in-silico prediction, not a clinical call.

AFF2 p.Arg853His

c.2558G>A · rs782648832 · VCV982732

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5308 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00889%, eas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

FRAXE intellectual disability

Computational evidence

Protein change
AlphaMissense	0.5308	ambiguous
REVEL	0.651	pathogenic-leaning
SaProt	LLR -8.12	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 304 kb · p 0.17 · regional, not allelic
Overall
CADD	26.3	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 0.00889% East Asian · 3/33,745 alleles

Filtering AF 0.00236% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00138%

Overall 0.0024% 29/1,207,087 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00889%	11,248
European (non-Finnish)	0.00246%	40,630
Finnishnot grpmax-eligible	0.00215%	46,610
Remaining individualsnot grpmax-eligible	0.00211%	47,454
South Asian	0.00179%	55,906
African / African-American	0.00175%	57,240

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.Arg853His
Coding: c.2558G>A
MANE Select: NM_002025
dbSNP: rs782648832
Type: single nucleotide variant
Location: chrX:148956603 (GRCh38)
Structure: AlphaFold pLDDT 49.27
Residue 853: 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 c.3267+5G>C Uncertain significance ★★ same condition
AFF2 p.Arg1238Cys 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-arg853his (accessed [today's date]).

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