Is AFF4 p.Ser843= (c.2529A>G) pathogenic?

AFF4 p.Ser843= (c.2529A>G) is classified Benign in AFF4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-08). Rare (popmax 0.127%, eas); Associated with cognitive impairment - coarse facies - heart defects - obesity - pulmonary involvement - short stature - skeletal dysplasia syndrome.

How common is AFF4 p.Ser843= (c.2529A>G) in the general population?

AFF4 p.Ser843= (c.2529A>G) is rare (popmax 0.127%, eas) (gnomAD).

AFF4 p.Ser843=

Q: What condition is associated with AFF4 p.Ser843= (c.2529A>G)?

AFF4 p.Ser843= (c.2529A>G) is associated with cognitive impairment - coarse facies - heart defects - obesity - pulmonary involvement - short stature - skeletal dysplasia syndrome (ClinVar).

c.2529A>G · rs201355729 · VCV1572260

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

rare (popmax 0.127%, 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	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.044	GERP -2.4, phastCons 0.81
Overall
CADD	6.708	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.127% East Asian · 57/44,862 alleles

Filtering AF 0.101% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0912%

Overall 0.00415% 67/1,614,092 alleles · rare exomes 50/1,461,876 · genomes 17/152,216 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.127%	787
Remaining individualsnot grpmax-eligible	0.0048%	20,836
Admixed American	0.00333%	30,003
South Asian	0.0022%	45,540
European (non-Finnish)	0.000254%	393,342

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.Ser843=
Coding: c.2529A>G
MANE Select: NM_014423
dbSNP: rs201355729
Type: single nucleotide variant
Location: chr5:132892272 (GRCh38)
Gene constraint: LOEUF 0.114 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 54.62 · 9 PDB
Residue 843: 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-ser843 (accessed [today's date]).

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