Is AFF4 p.Lys747Arg (c.2240A>G) pathogenic?

AFF4 p.Lys747Arg (c.2240A>G) is classified Conflicting classifications of pathogenicity in AFF4 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-09-18). AlphaMissense: likely benign (0.0955); Ultra-rare (popmax 0.0143%, sas); Associated with Inborn genetic diseases.

How common is AFF4 p.Lys747Arg (c.2240A>G) in the general population?

AFF4 p.Lys747Arg (c.2240A>G) is ultra-rare (popmax 0.0143%, sas) (gnomAD).

What do computational predictors say about AFF4 p.Lys747Arg (c.2240A>G)?

AlphaMissense predicts likely benign (score 0.0955) — an in-silico prediction, not a clinical call.

AFF4 p.Lys747Arg

Q: What condition is associated with AFF4 p.Lys747Arg (c.2240A>G)?

AFF4 p.Lys747Arg (c.2240A>G) is associated with Inborn genetic diseases, cognitive impairment - coarse facies - heart defects - obesity - pulmonary involvement - short stature - skeletal dysplasia syndrome (ClinVar).

c.2240A>G · rs201536066 · VCV2174433

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0955 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0143%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0955	likely benign
REVEL	0.174	moderately benign-leaning
SaProt	LLR -7.58	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8	GERP 5.2, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 7,535 bp · p 0.44 · regional, not allelic
Overall
CADD	22.8	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 0.0143% South Asian · 13/90,986 alleles

Filtering AF 0.00845% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00662%

Overall 0.00297% 48/1,613,678 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0143%	6,999
Admixed American	0.00501%	19,953
Remaining individualsnot grpmax-eligible	0.0048%	20,825
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,590
European (non-Finnish)	0.00237%	42,141

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.Lys747Arg
Coding: c.2240A>G
MANE Select: NM_014423
dbSNP: rs201536066
Type: single nucleotide variant
Location: chr5:132896390 (GRCh38)
Gene constraint: LOEUF 0.114 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 54.62 · 9 PDB
Residue 747: the 'disordered' region

Full AFF4 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

Also linked: cognitive impairment - coarse facies - heart defects - obesity - pulmonary involvement - short stature - skeletal dysplasia syndrome

Similar variants

AFF4 p.Arg258Trp Pathogenic/Likely pathogenic ★★ ⚠ same condition
AFF4 p.Met260Val Likely pathogenic ★★ ⚠ same condition
AFF4 p.Pro253Leu Pathogenic/Likely pathogenic ★★ ⚠ same condition
AFF4 p.Thr254Ser Pathogenic/Likely pathogenic ★★ ⚠ same condition
AFF4 c.1133+3A>G Uncertain significance ★★ same condition
AFF4 p.Ala114Thr Uncertain significance ★★ ⚠ same condition
AFF4 p.Ala114Val Uncertain significance ★★ ⚠ same condition
AFF4 p.Ala27Thr 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-lys747arg (accessed [today's date]).

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