Is AFF2 p.Thr727= (c.2181C>T) pathogenic?

AFF2 p.Thr727= (c.2181C>T) is classified Benign/Likely benign in AFF2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-12-01). Rare (popmax 0.418%, afr).

How common is AFF2 p.Thr727= (c.2181C>T) in the general population?

AFF2 p.Thr727= (c.2181C>T) is rare (popmax 0.418%, afr) (gnomAD).

AFF2 p.Thr727=

c.2181C>T · rs143927826 · VCV501386

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

rare (popmax 0.418%, afr)

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 0.74	GERP -2.5, phastCons 0.7
Overall
CADD	4.936	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.418% African / African-American · 238/56,952 alleles

Filtering AF 0.374% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.357%

Overall 0.0215% 260/1,209,298 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.418%	239
Remaining individualsnot grpmax-eligible	0.0294%	3,401
Admixed American	0.0175%	5,711

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.Thr727=
Coding: c.2181C>T
MANE Select: NM_002025
dbSNP: rs143927826
Type: single nucleotide variant
Location: chrX:148956226 (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-thr727 (accessed [today's date]).

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