Is AFF4 p.Pro223Ala (c.667C>G) pathogenic?

AFF4 p.Pro223Ala (c.667C>G) is classified Uncertain significance in AFF4 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-01-25). AlphaMissense: likely benign (0.2592); Very rare (popmax 0.000169%, nfe); Associated with AFF4-related disorder.

What condition is associated with AFF4 p.Pro223Ala (c.667C>G)?

AFF4 p.Pro223Ala (c.667C>G) is associated with AFF4-related disorder (ClinVar).

How common is AFF4 p.Pro223Ala (c.667C>G) in the general population?

AFF4 p.Pro223Ala (c.667C>G) is very rare (popmax 0.000169%, nfe) (gnomAD).

What do computational predictors say about AFF4 p.Pro223Ala (c.667C>G)?

AlphaMissense predicts likely benign (score 0.2592) — an in-silico prediction, not a clinical call.

AFF4 p.Pro223Ala

c.667C>G · rs1761371602 · VCV3047281

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2592 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

AFF4-related disorder

Computational evidence

Protein change
AlphaMissense	0.2592	likely benign
REVEL	0.316	indeterminate
SaProt	LLR -6.48	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 4, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 477 bp · p 0.29 · regional, not allelic
Overall
CADD	25.5	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 0.000169% European (non-Finnish) · 2/1,180,026 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,461,886 alleles · very rare

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: AFF4
Protein: p.Pro223Ala
Coding: c.667C>G
MANE Select: NM_014423
dbSNP: rs1761371602
Type: single nucleotide variant
Location: chr5:132934398 (GRCh38)
Gene constraint: LOEUF 0.114 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 54.62 · 9 PDB
Residue 223: the 'disordered' region

Full AFF4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

AFF4-related disorder

Similar variants

AFF4 p.Pro223Leu Uncertain significance ★ ⚠ same residue
AFF4 p.Glu657Asp Uncertain significance ★★ ⚠ same condition
AFF4 p.Ser839Cys Uncertain significance ★★ ⚠ same condition
AFF4 p.Ala551Thr Uncertain significance ★ ⚠ same condition
AFF4 p.Arg209Ser Uncertain significance ★ ⚠ same condition
AFF4 p.Arg725Lys Uncertain significance ★ ⚠ same condition
AFF4 p.Asp422Gly Uncertain significance ★ ⚠ same condition
AFF4 p.Pro611Leu 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/aff4-p-pro223ala (accessed [today's date]).

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