Is AFF2 p.Pro261Ser (c.781C>T) pathogenic?

AFF2 p.Pro261Ser (c.781C>T) is classified Uncertain significance in AFF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2015-11-25). AlphaMissense: likely benign (0.1058); Very rare (popmax 0.00877%, sas).

How common is AFF2 p.Pro261Ser (c.781C>T) in the general population?

AFF2 p.Pro261Ser (c.781C>T) is very rare (popmax 0.00877%, sas) (gnomAD).

What do computational predictors say about AFF2 p.Pro261Ser (c.781C>T)?

AlphaMissense predicts likely benign (score 0.1058) — an in-silico prediction, not a clinical call.

AFF2 p.Pro261Ser

c.781C>T · rs886044832 · VCV284703

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1058 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00877%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1058	likely benign
REVEL	0.132	moderately benign-leaning
SaProt	LLR -5.53	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 2.8	GERP 2.5, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 161 kb · p 0.93 · 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

Grpmax group 0.00877% South Asian · 5/57,009 alleles

Filtering AF 0.00339% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00216%

Overall 0.000546% 6/1,098,258 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00877%	11,402
Remaining individualsnot grpmax-eligible	0.0021%	47,654

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.Pro261Ser
Coding: c.781C>T
MANE Select: NM_002025
dbSNP: rs886044832
Type: single nucleotide variant
Location: chrX:148662508 (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-pro261ser (accessed [today's date]).

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