Is AFF2 p.Ser496= (c.1488G>A) pathogenic?

AFF2 p.Ser496= (c.1488G>A) is classified Benign in AFF2 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2025-11-14). Common (popmax 39.9%, afr) — too common for a highly-penetrant pathogenic allele; Associated with FRAXE intellectual disability.

What condition is associated with AFF2 p.Ser496= (c.1488G>A)?

AFF2 p.Ser496= (c.1488G>A) is associated with FRAXE intellectual disability (ClinVar).

How is FRAXE intellectual disability inherited?

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

AFF2 p.Ser496=

Q: How common is AFF2 p.Ser496= (c.1488G>A) in the general population?

AFF2 p.Ser496= (c.1488G>A) is common (popmax 39.9%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1488G>A · rs12011040 · VCV128281

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

gnomAD v4.1

Common

common (popmax 39.9%, afr) — too common for a highly-penetrant pathogenic allele

Conditions

FRAXE intellectual disability

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -7.6	GERP -3.9
Overall
CADD	0.119	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 39.9% African / African-American · 22,574/56,524 alleles

Filtering AF 39.5% ClinGen BA1/BS1 input FAF95, joint · FAF99 39.3%

Overall 5.57% 67,293/1,208,514 alleles · common exomes 51,804/1,097,707 · genomes 15,489/110,807 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	39.9%	3
Amishnot grpmax-eligible	22.8%	4
Ashkenazi Jewishnot grpmax-eligible	7.49%	13
Middle Eastern	6.65%	15
Remaining individualsnot grpmax-eligible	6.35%	16
Finnishnot grpmax-eligible	6.24%	16
Admixed American	4.04%	25
European (non-Finnish)	3.68%	27
South Asian	3.32%	30
East Asian	0.13%	766

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.Ser496=
Coding: c.1488G>A
MANE Select: NM_002025
dbSNP: rs12011040
Type: single nucleotide variant
Location: chrX:148953670 (GRCh38)
Structure: AlphaFold pLDDT 49.27
Residue 496: 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.Ser496Leu Uncertain significance ★★ ⚠ same residue
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

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-ser496 (accessed [today's date]).

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