Is AFF4 p.Ala816Thr (c.2446G>A) pathogenic?

AFF4 p.Ala816Thr (c.2446G>A) is classified Conflicting classifications of pathogenicity in AFF4 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-01-06). AlphaMissense: likely benign (0.0651); Ultra-rare (popmax 0.0223%, eas); Associated with cognitive impairment - coarse facies - heart defects - obesity - pulmonary involvement - short stature - skeletal dysplasia syndrome.

How common is AFF4 p.Ala816Thr (c.2446G>A) in the general population?

AFF4 p.Ala816Thr (c.2446G>A) is ultra-rare (popmax 0.0223%, eas) (gnomAD).

What do computational predictors say about AFF4 p.Ala816Thr (c.2446G>A)?

AlphaMissense predicts likely benign (score 0.0651) — an in-silico prediction, not a clinical call.

AFF4 p.Ala816Thr

Q: What condition is associated with AFF4 p.Ala816Thr (c.2446G>A)?

AFF4 p.Ala816Thr (c.2446G>A) is associated with cognitive impairment - coarse facies - heart defects - obesity - pulmonary involvement - short stature - skeletal dysplasia syndrome (ClinVar).

c.2446G>A · rs750323931 · VCV1347626

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0651 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0223%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

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

Computational evidence

Protein change
AlphaMissense	0.0651	likely benign
REVEL	0.157	moderately benign-leaning
SaProt	LLR -5.89	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.4	GERP 4.8, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 7,535 bp · p 0.44 · regional, not allelic
Overall
CADD	22.8	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0223% East Asian · 10/44,870 alleles

Filtering AF 0.012% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00917%

Overall 0.00372% 60/1,613,890 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0223%	4,487
Admixed American	0.0183%	5,455
Middle Eastern	0.0165%	6,050
South Asian	0.00878%	11,386
Remaining individualsnot grpmax-eligible	0.0064%	15,625
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,596
European (non-Finnish)	0.00212%	47,195

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.Ala816Thr
Coding: c.2446G>A
MANE Select: NM_014423
dbSNP: rs750323931
Type: single nucleotide variant
Location: chr5:132892355 (GRCh38)
Gene constraint: LOEUF 0.114 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 54.62 · 9 PDB
Residue 816: 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.Ala816Ser 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-ala816thr (accessed [today's date]).

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