Is AFF2 p.Ile703Met (c.2109T>G) pathogenic?

AFF2 p.Ile703Met (c.2109T>G) is classified Uncertain significance in AFF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-07). AlphaMissense: likely benign (0.0649); Ultra-rare (popmax 0.0212%, afr); Associated with Inborn genetic diseases.

What condition is associated with AFF2 p.Ile703Met (c.2109T>G)?

AFF2 p.Ile703Met (c.2109T>G) is associated with Inborn genetic diseases (ClinVar).

How common is AFF2 p.Ile703Met (c.2109T>G) in the general population?

AFF2 p.Ile703Met (c.2109T>G) is ultra-rare (popmax 0.0212%, afr) (gnomAD).

What do computational predictors say about AFF2 p.Ile703Met (c.2109T>G)?

AlphaMissense predicts likely benign (score 0.0649) — an in-silico prediction, not a clinical call.

AFF2 p.Ile703Met

c.2109T>G · VCV4021626

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0649 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0212%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0649	likely benign
REVEL	0.174	moderately benign-leaning
SaProt	LLR -7.22	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 -7.7	GERP -3.6
Regional constraint	o/e 0.94	unconstrained · MANE · 304 kb · p 0.17 · regional, not allelic
Overall
CADD	1.951	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 0.0212% African / African-American · 12/56,674 alleles

Filtering AF 0.0121% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00957%

Overall 0.00174% 21/1,208,356 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0212%	4,723
Remaining individualsnot grpmax-eligible	0.0189%	5,290

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.Ile703Met
Coding: c.2109T>G
MANE Select: NM_002025
Type: single nucleotide variant
Location: chrX:148956154 (GRCh38)
Structure: AlphaFold pLDDT 49.27
Residue 703: the 'disordered' region

Full AFF2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

AFF2 p.Ala1197Thr Uncertain significance ★★ ⚠ same condition
AFF2 p.Arg1295Cys Uncertain significance ★★ ⚠ same condition
AFF2 p.Asp187Glu Uncertain significance ★★ ⚠ same condition
AFF2 p.Gln205Lys Uncertain significance ★★ ⚠ same condition
AFF2 p.Gly482Arg Uncertain significance ★★ ⚠ same condition
AFF2 p.Gly740Val Uncertain significance ★★ ⚠ same condition
AFF2 p.His1070Arg Uncertain significance ★★ ⚠ same condition
AFF2 p.His366Arg 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-ile703met (accessed [today's date]).

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