Is AFF2 p.Pro138Ala (c.412C>G) pathogenic?

AFF2 p.Pro138Ala (c.412C>G) is classified Uncertain significance in AFF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-09-11). AlphaMissense: likely benign (0.1083); Very rare (popmax 0.00481%, nfe); Associated with FRAXE intellectual disability.

What condition is associated with AFF2 p.Pro138Ala (c.412C>G)?

AFF2 p.Pro138Ala (c.412C>G) is associated with FRAXE intellectual disability (ClinVar).

How common is AFF2 p.Pro138Ala (c.412C>G) in the general population?

AFF2 p.Pro138Ala (c.412C>G) is very rare (popmax 0.00481%, 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.Pro138Ala (c.412C>G)?

AlphaMissense predicts likely benign (score 0.1083) — an in-silico prediction, not a clinical call.

AFF2 p.Pro138Ala

c.412C>G · rs782277853 · VCV2438906

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1083 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00481%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

FRAXE intellectual disability

Computational evidence

Protein change
AlphaMissense	0.1083	likely benign
REVEL	0.277	benign-leaning
SaProt	LLR -6.90	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 1.8	GERP 1.6, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 161 kb · p 0.93 · regional, not allelic
Overall
CADD	22.5	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 0.00481% European (non-Finnish) · 43/893,863 alleles

Filtering AF 0.00362% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00322%

Overall 0.00429% 47/1,096,411 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0084%	11,900
European (non-Finnish)grpmax	0.00481%	20,788

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro138Ala
Coding: c.412C>G
MANE Select: NM_002025
dbSNP: rs782277853
Type: single nucleotide variant
Location: chrX:148662139 (GRCh38)
Structure: AlphaFold pLDDT 49.27
Residue 138: 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-pro138ala (accessed [today's date]).

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