Is AFF1 p.Gln1147Pro (c.3440A>C) pathogenic?

AFF1 p.Gln1147Pro (c.3440A>C) is classified Uncertain significance in AFF1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-11). AlphaMissense: likely benign (0.126); Very rare (popmax 0.000169%, nfe).

How common is AFF1 p.Gln1147Pro (c.3440A>C) in the general population?

AFF1 p.Gln1147Pro (c.3440A>C) is very rare (popmax 0.000169%, nfe) (gnomAD).

What do computational predictors say about AFF1 p.Gln1147Pro (c.3440A>C)?

AlphaMissense predicts likely benign (score 0.126) — an in-silico prediction, not a clinical call.

AFF1 p.Gln1147Pro

c.3440A>C · VCV3503718

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.126 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.126	likely benign
REVEL	0.351	indeterminate
SaProt	LLR -13.52	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.2	GERP 2.5, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 4,557 bp · p 0.14 · regional, not allelic
Overall
CADD	18.0	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 Q1139P vs ClinVar Q1147P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000169% European (non-Finnish) · 2/1,180,040 alleles

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

Overall 0.000137% 2/1,461,874 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: AFF1
Protein: p.Gln1147Pro
Coding: c.3440A>C
MANE Select: NM_001166693
Type: single nucleotide variant
Location: chr4:87134599 (GRCh38)
Gene constraint: LOEUF 0.49 · pLI 0.95 (gnomAD)
Structure: AlphaFold pLDDT 53.06 · 1 PDB

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-gln1147pro (accessed [today's date]).

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