Is AFF2 p.Pro886Ala (c.2656C>G) pathogenic?

AFF2 p.Pro886Ala (c.2656C>G) is classified Benign/Likely benign in AFF2 (ClinVar, Multiple submitters, 14 submitters; last evaluated 2024-11-25). AlphaMissense: likely benign (0.1441); Rare (popmax 0.191%, nfe); Associated with FRAXE intellectual disability.

What condition is associated with AFF2 p.Pro886Ala (c.2656C>G)?

AFF2 p.Pro886Ala (c.2656C>G) is associated with FRAXE intellectual disability, intellectual disability (ClinVar).

How common is AFF2 p.Pro886Ala (c.2656C>G) in the general population?

AFF2 p.Pro886Ala (c.2656C>G) is rare (popmax 0.191%, 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.Pro886Ala (c.2656C>G)?

AlphaMissense predicts likely benign (score 0.1441) — an in-silico prediction, not a clinical call.

AFF2 p.Pro886Ala

c.2656C>G · rs151043891 · VCV166659

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 14 submitters

AlphaMissense

likely benign

0.1441 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.191%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

FRAXE intellectual disability

Computational evidence

Protein change
AlphaMissense	0.1441	likely benign
REVEL	0.207	benign-leaning
SaProt	LLR -7.76	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 7.5	GERP 1.8, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 304 kb · p 0.17 · regional, not allelic
Overall
CADD	24.1	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 0.191% European (non-Finnish) · 1,709/894,776 alleles

Filtering AF 0.183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.18%

Overall 0.159% 1,927/1,209,004 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.191%	524
Admixed American	0.182%	550
Remaining individualsnot grpmax-eligible	0.132%	755
Finnishnot grpmax-eligible	0.125%	802
African / African-American	0.0246%	4,073

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.Pro886Ala
Coding: c.2656C>G
MANE Select: NM_002025
dbSNP: rs151043891
Type: single nucleotide variant
Location: chrX:148958424 (GRCh38)
Structure: AlphaFold pLDDT 49.27
Residue 886: 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

Also linked: intellectual disability

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-pro886ala (accessed [today's date]).

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