Is AFF2 p.Ile309Thr (c.926T>C) pathogenic?

AFF2 p.Ile309Thr (c.926T>C) is classified Uncertain significance in AFF2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2016-11-10). AlphaMissense: likely benign (0.0879); Very rare (popmax 0.0035%, afr).

How common is AFF2 p.Ile309Thr (c.926T>C) in the general population?

AFF2 p.Ile309Thr (c.926T>C) is very rare (popmax 0.0035%, afr) (gnomAD).

What do computational predictors say about AFF2 p.Ile309Thr (c.926T>C)?

AlphaMissense predicts likely benign (score 0.0879) — an in-silico prediction, not a clinical call.

AFF2 p.Ile309Thr

c.926T>C · rs782518861 · VCV376872

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0879 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0035%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0879	likely benign
REVEL	0.185	benign-leaning
SaProt	LLR -5.44	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 1.9	GERP 1.5, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 304 kb · p 0.17 · regional, not allelic
Overall
CADD	20.4	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 0.0035% African / African-American · 2/57,191 alleles

Filtering AF 0.00058% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000217%

Overall 0.000661% 8/1,210,304 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0035%	28,596
South Asian	0.00176%	56,833
European (non-Finnish)	0.000558%	179,065

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.Ile309Thr
Coding: c.926T>C
MANE Select: NM_002025
dbSNP: rs782518861
Type: single nucleotide variant
Location: chrX:148662653 (GRCh38)
Structure: AlphaFold pLDDT 49.27

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

Similar variants

AFF2 c.3267+5G>C Uncertain significance ★★ same type
AFF2 p.Ala1197Thr Uncertain significance ★★ ⚠ same type
AFF2 p.Ala171Pro Uncertain significance ★★ ⚠ same type
AFF2 p.Arg1238Cys Uncertain significance ★★ ⚠ same type
AFF2 p.Arg1295Cys Uncertain significance ★★ ⚠ same type
AFF2 p.Arg670His Uncertain significance ★★ ⚠ same type
AFF2 p.Asn77Ile Uncertain significance ★★ ⚠ same type
AFF2 p.Asp187Glu Uncertain significance ★★ ⚠ same type

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-ile309thr (accessed [today's date]).

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