Is AFF4 p.Arg750= (c.2250A>G) pathogenic?

AFF4 p.Arg750= (c.2250A>G) is classified Likely benign in AFF4 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-05-28). Very rare (popmax 0.0011%, nfe); Associated with cognitive impairment - coarse facies - heart defects - obesity - pulmonary involvement - short stature - skeletal dysplasia syndrome.

How common is AFF4 p.Arg750= (c.2250A>G) in the general population?

AFF4 p.Arg750= (c.2250A>G) is very rare (popmax 0.0011%, nfe) (gnomAD).

AFF4 p.Arg750=

Q: What condition is associated with AFF4 p.Arg750= (c.2250A>G)?

AFF4 p.Arg750= (c.2250A>G) is associated with cognitive impairment - coarse facies - heart defects - obesity - pulmonary involvement - short stature - skeletal dysplasia syndrome (ClinVar).

c.2250A>G · rs763815070 · VCV1545916

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.0011%, nfe)

Conditions

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

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.1	GERP 5.2, phastCons 1
Overall
CADD	11.44	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% European (non-Finnish) · 13/1,179,790 alleles

Filtering AF 0.000615% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000474%

Overall 0.00093% 15/1,612,866 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0032%	31,204
European (non-Finnish)grpmax	0.0011%	90,753

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg750=
Coding: c.2250A>G
MANE Select: NM_014423
dbSNP: rs763815070
Type: single nucleotide variant
Location: chr5:132896380 (GRCh38)
Gene constraint: LOEUF 0.114 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 54.62 · 9 PDB
Residue 750: the 'disordered' region

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

Disease context

cognitive impairment - coarse facies - heart defects - obesity - pulmonary involvement - short stature - skeletal dysplasia syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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-arg750 (accessed [today's date]).

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