Is AFF4 p.Thr1107= (c.3321C>T) pathogenic?

AFF4 p.Thr1107= (c.3321C>T) is classified Benign in AFF4 (ClinVar, Single submitter, 2 submitters; last evaluated 2021-07-13). Ultra-rare (popmax 0.0668%, eas); Associated with cognitive impairment - coarse facies - heart defects - obesity - pulmonary involvement - short stature - skeletal dysplasia syndrome.

How common is AFF4 p.Thr1107= (c.3321C>T) in the general population?

AFF4 p.Thr1107= (c.3321C>T) is ultra-rare (popmax 0.0668%, eas) (gnomAD).

AFF4 p.Thr1107=

Q: What condition is associated with AFF4 p.Thr1107= (c.3321C>T)?

AFF4 p.Thr1107= (c.3321C>T) is associated with cognitive impairment - coarse facies - heart defects - obesity - pulmonary involvement - short stature - skeletal dysplasia syndrome (ClinVar).

c.3321C>T · rs745754457 · VCV1659713

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0668%, eas)

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 -2.7	GERP -12
Overall
CADD	0.571	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0668% East Asian · 30/44,884 alleles

Filtering AF 0.0481% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0417%

Overall 0.00347% 56/1,613,912 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0668%	1,496
Admixed American	0.00666%	15,005
Remaining individualsnot grpmax-eligible	0.0048%	20,834
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,604
South Asian	0.00329%	30,355
African / African-American	0.00133%	75,002
European (non-Finnish)	0.00119%	84,285

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.Thr1107=
Coding: c.3321C>T
MANE Select: NM_014423
dbSNP: rs745754457
Type: single nucleotide variant
Location: chr5:132883383 (GRCh38)
Gene constraint: LOEUF 0.114 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 54.62 · 9 PDB
Residue 1107: an α-helix

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.Thr1107Ala Benign/Likely benign ★★ same residue
AFF4 p.Thr1107Asn Uncertain significance ★ ⚠ same residue
AFF4 p.Thr1107Ile 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

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-thr1107 (accessed [today's date]).

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