Is AFF4 p.Glu758= (c.2274A>G) pathogenic?

AFF4 p.Glu758= (c.2274A>G) is classified Likely benign in AFF4 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-10-19). Ultra-rare (popmax 0.0108%, nfe); Associated with cognitive impairment - coarse facies - heart defects - obesity - pulmonary involvement - short stature - skeletal dysplasia syndrome.

How common is AFF4 p.Glu758= (c.2274A>G) in the general population?

AFF4 p.Glu758= (c.2274A>G) is ultra-rare (popmax 0.0108%, nfe) (gnomAD).

AFF4 p.Glu758=

Q: What condition is associated with AFF4 p.Glu758= (c.2274A>G)?

AFF4 p.Glu758= (c.2274A>G) is associated with cognitive impairment - coarse facies - heart defects - obesity - pulmonary involvement - short stature - skeletal dysplasia syndrome (ClinVar).

c.2274A>G · rs766764087 · VCV2149067

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0108%, 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 -0.009	GERP 0.28, phastCons 0.9
Overall
CADD	5.87	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0108% European (non-Finnish) · 127/1,176,130 alleles

Filtering AF 0.00922% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00866%

Overall 0.00857% 137/1,598,172 alleles · ultra-rare exomes 130/1,445,912 · genomes 7/152,260 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0108%	9,261
Remaining individualsnot grpmax-eligible	0.00973%	10,279
South Asian	0.00456%	21,944

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.Glu758=
Coding: c.2274A>G
MANE Select: NM_014423
dbSNP: rs766764087
Type: single nucleotide variant
Location: chr5:132896356 (GRCh38)
Gene constraint: LOEUF 0.114 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 54.62 · 9 PDB
Residue 758: 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.Glu758Lys Uncertain significance ★ ⚠ same residue
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

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-glu758 (accessed [today's date]).

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