Is AFF4 p.Arg209Ser (c.625C>A) pathogenic?

AFF4 p.Arg209Ser (c.625C>A) is classified Uncertain significance in AFF4 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-22). AlphaMissense: likely pathogenic (0.61); Absent from gnomAD v4.1; Associated with AFF4-related disorder.

What condition is associated with AFF4 p.Arg209Ser (c.625C>A)?

AFF4 p.Arg209Ser (c.625C>A) is associated with AFF4-related disorder (ClinVar).

How common is AFF4 p.Arg209Ser (c.625C>A) in the general population?

AFF4 p.Arg209Ser (c.625C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about AFF4 p.Arg209Ser (c.625C>A)?

AlphaMissense predicts likely pathogenic (score 0.61) — an in-silico prediction, not a clinical call.

AFF4 p.Arg209Ser

c.625C>A · rs776597233 · VCV2636866

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.61 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

AFF4-related disorder

Computational evidence

Protein change
AlphaMissense	0.61	likely pathogenic
REVEL	0.179	moderately benign-leaning
SaProt	LLR -6.35	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
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	27.2	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: AFF4
Protein: p.Arg209Ser
Coding: c.625C>A
MANE Select: NM_014423
dbSNP: rs776597233
Type: single nucleotide variant
Location: chr5:132934440 (GRCh38)
Gene constraint: LOEUF 0.114 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 54.62 · 9 PDB
Residue 209: 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.Arg209His 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.Arg725Lys Uncertain significance ★ ⚠ same condition
AFF4 p.Asp422Gly Uncertain significance ★ ⚠ same condition
AFF4 p.Pro611Leu Uncertain significance ★ ⚠ same condition
AFF4 p.Ser1077Phe 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-arg209ser (accessed [today's date]).

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