Is AFF4 p.Lys964= (c.2892A>G) pathogenic?

AFF4 p.Lys964= (c.2892A>G) is classified Benign/Likely benign in AFF4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-02-01). Low-frequency (popmax 2.79%, afr); Associated with cognitive impairment - coarse facies - heart defects - obesity - pulmonary involvement - short stature - skeletal dysplasia syndrome.

How common is AFF4 p.Lys964= (c.2892A>G) in the general population?

AFF4 p.Lys964= (c.2892A>G) is low-frequency (popmax 2.79%, afr) (gnomAD).

AFF4 p.Lys964=

Q: What condition is associated with AFF4 p.Lys964= (c.2892A>G)?

AFF4 p.Lys964= (c.2892A>G) is associated with cognitive impairment - coarse facies - heart defects - obesity - pulmonary involvement - short stature - skeletal dysplasia syndrome (ClinVar).

c.2892A>G · rs34434281 · VCV707057

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

low-frequency (popmax 2.79%, afr)

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 0.008	GERP -0.056, phastCons 0.93
Overall
CADD	6.508	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 2.79% African / African-American · 2,089/75,000 alleles

Filtering AF 2.69% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.65%

Overall 0.225% 3,627/1,613,886 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	2.79%	36
Ashkenazi Jewishnot grpmax-eligible	1.21%	82
Admixed American	0.667%	150
Middle Eastern	0.512%	195
Remaining individualsnot grpmax-eligible	0.464%	215
European (non-Finnish)	0.0384%	2,605
South Asian	0.00549%	18,214

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.Lys964=
Coding: c.2892A>G
MANE Select: NM_014423
dbSNP: rs34434281
Type: single nucleotide variant
Location: chr5:132887887 (GRCh38)
Gene constraint: LOEUF 0.114 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 54.62 · 9 PDB

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-lys964 (accessed [today's date]).

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