Is AFF3 p.Pro1117Ala (c.3349C>G) pathogenic?

AFF3 p.Pro1117Ala (c.3349C>G) is classified Uncertain significance in AFF3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-02). AlphaMissense: likely benign (0.1864); Ultra-rare (popmax 0.0347%, afr); Associated with Inborn genetic diseases.

What condition is associated with AFF3 p.Pro1117Ala (c.3349C>G)?

AFF3 p.Pro1117Ala (c.3349C>G) is associated with Inborn genetic diseases (ClinVar).

How common is AFF3 p.Pro1117Ala (c.3349C>G) in the general population?

AFF3 p.Pro1117Ala (c.3349C>G) is ultra-rare (popmax 0.0347%, afr) (gnomAD).

What do computational predictors say about AFF3 p.Pro1117Ala (c.3349C>G)?

AlphaMissense predicts likely benign (score 0.1864) — an in-silico prediction, not a clinical call.

AFF3 p.Pro1117Ala

c.3349C>G · rs200197052 · VCV3092622

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1864 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0347%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1864	likely benign
REVEL	0.688	pathogenic-leaning
SaProt	LLR -7.69	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>A here scores Δ0.22 · evaluated, not missing
Constraint at this position
Conservation	phyloP 9.9	GERP 1, phastCons 1
Regional constraint	o/e 0.71	unconstrained · MANE · 8,927 bp · p 6.5e-06 · regional, not allelic
Overall
CADD	26.3	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

Grpmax group 0.0347% African / African-American · 26/75,030 alleles

Filtering AF 0.0242% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0208%

Overall 0.00161% 26/1,613,130 alleles · ultra-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: AFF3
Protein: p.Pro1117Ala
Coding: c.3349C>G
MANE Select: NM_001386135
dbSNP: rs200197052
Type: single nucleotide variant
Location: chr2:99554521 (GRCh38)
Gene constraint: LOEUF 0.318 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 52.20
Residue 1117: the 'disordered' region

Full AFF3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

AFF3 p.Ala233Thr Pathogenic ★★ ⚠ same condition
AFF3 p.Ile1147Asn Uncertain significance ★★ ⚠ same condition
AFF3 p.Leu370Phe Uncertain significance ★★ ⚠ same condition
AFF3 p.Pro321Leu Uncertain significance ★★ ⚠ same condition
AFF3 p.Ser222Thr Uncertain significance ★★ ⚠ same condition
AFF3 p.Thr950Met Uncertain significance ★★ ⚠ same condition
AFF3 p.Ala1100Val Uncertain significance ★ ⚠ same condition
AFF3 p.Ala1103Thr 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/aff3-p-pro1117ala (accessed [today's date]).

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