Is AFF2 p.Leu323Phe (c.967C>T) pathogenic?

AFF2 p.Leu323Phe (c.967C>T) is classified Uncertain significance in AFF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-10). AlphaMissense: likely benign (0.1049); Absent from gnomAD v4.1; Associated with FRAXE intellectual disability.

What condition is associated with AFF2 p.Leu323Phe (c.967C>T)?

AFF2 p.Leu323Phe (c.967C>T) is associated with FRAXE intellectual disability (ClinVar).

How common is AFF2 p.Leu323Phe (c.967C>T) in the general population?

AFF2 p.Leu323Phe (c.967C>T) is absent from gnomAD v4.1 (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.Leu323Phe (c.967C>T)?

AlphaMissense predicts likely benign (score 0.1049) — an in-silico prediction, not a clinical call.

AFF2 p.Leu323Phe

c.967C>T · VCV3377354

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1049 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

FRAXE intellectual disability

Computational evidence

Protein change
AlphaMissense	0.1049	likely benign
REVEL	0.24	benign-leaning
SaProt	LLR -6.96	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 3.3	GERP 1.7, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 304 kb · p 0.17 · regional, not allelic
Overall
CADD	22.7	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: AFF2
Protein: p.Leu323Phe
Coding: c.967C>T
MANE Select: NM_002025
Type: single nucleotide variant
Location: chrX:148662694 (GRCh38)
Structure: AlphaFold pLDDT 49.27

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-leu323phe (accessed [today's date]).

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