Is AFF1 p.Pro1109Leu (c.3326C>T) pathogenic?

AFF1 p.Pro1109Leu (c.3326C>T) is classified Uncertain significance in AFF1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-08). AlphaMissense: likely benign (0.1558); Very rare (popmax 0.00987%, nfe).

How common is AFF1 p.Pro1109Leu (c.3326C>T) in the general population?

AFF1 p.Pro1109Leu (c.3326C>T) is very rare (popmax 0.00987%, nfe) (gnomAD).

What do computational predictors say about AFF1 p.Pro1109Leu (c.3326C>T)?

AlphaMissense predicts likely benign (score 0.1558) — an in-silico prediction, not a clinical call.

AFF1 p.Pro1109Leu

c.3326C>T · rs755513702 · VCV2325776

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1558 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00987%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1558	likely benign
REVEL	0.814	moderately pathogenic-leaning
SaProt	LLR -7.66	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP 1.6, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 4,557 bp · p 0.14 · regional, not allelic
Overall
CADD	23.7	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P1101L vs ClinVar P1109L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00987% European (non-Finnish) · 116/1,174,746 alleles

Filtering AF 0.00838% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0078%

Overall 0.00761% 122/1,602,718 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00987%	10,127
Remaining individualsnot grpmax-eligible	0.00645%	15,497
African / African-American	0.00134%	74,714
South Asian	0.00112%	89,172

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: AFF1
Protein: p.Pro1109Leu
Coding: c.3326C>T
MANE Select: NM_001166693
dbSNP: rs755513702
Type: single nucleotide variant
Location: chr4:87134485 (GRCh38)
Gene constraint: LOEUF 0.49 · pLI 0.95 (gnomAD)
Structure: AlphaFold pLDDT 53.06 · 1 PDB
Residue 1109: the 'disordered' region

Full AFF1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

AFF1 c.1191+8C>T Benign/Likely benign ★★ same type
AFF1 p.Ala40= Benign ★★ same type
AFF1 p.Pro393= Benign ★★ same type
AFF1 p.Ser627Cys Likely benign ★★ ⚠ same type
AFF1 p.Thr426= Likely benign ★★ same type
AFF1 p.Val711Ile Benign ★★ same type
AFF1 p.Ala1047Val Uncertain significance ★ ⚠ same type
AFF1 p.Ala1103Thr 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/aff1-p-pro1109leu (accessed [today's date]).

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