Is AFF3 p.Val259Met (c.775G>A) pathogenic?

AFF3 p.Val259Met (c.775G>A) is classified Conflicting classifications of pathogenicity in AFF3 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-11-22). AlphaMissense: likely benign (0.0807); Ultra-rare (popmax 0.0344%, nfe); Associated with Inborn genetic diseases.

What condition is associated with AFF3 p.Val259Met (c.775G>A)?

AFF3 p.Val259Met (c.775G>A) is associated with Inborn genetic diseases (ClinVar).

How common is AFF3 p.Val259Met (c.775G>A) in the general population?

AFF3 p.Val259Met (c.775G>A) is ultra-rare (popmax 0.0344%, nfe) (gnomAD).

What do computational predictors say about AFF3 p.Val259Met (c.775G>A)?

AlphaMissense predicts likely benign (score 0.0807) — an in-silico prediction, not a clinical call.

AFF3 p.Val259Met

c.775G>A · rs200905671 · VCV3092660

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0807 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0344%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0807	likely benign
REVEL	0.034	moderately benign-leaning
SaProt	LLR -8.04	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 0.23	GERP -2.9, phastCons 0.008
Regional constraint	o/e 0.97	unconstrained · MANE · 413 kb · p 0.58 · regional, not allelic
Overall
CADD	13.53	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 0.0344% European (non-Finnish) · 406/1,180,022 alleles

Filtering AF 0.0316% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0305%

Overall 0.0272% 439/1,614,082 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0344%	2,906
Remaining individualsnot grpmax-eligible	0.0256%	3,905
African / African-American	0.0133%	7,495
Admixed American	0.005%	20,003
East Asian	0.00223%	44,896
South Asian	0.0022%	45,545
Finnishnot grpmax-eligible	0.00156%	64,032

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: AFF3
Protein: p.Val259Met
Coding: c.775G>A
MANE Select: NM_001386135
dbSNP: rs200905671
Type: single nucleotide variant
Location: chr2:100006730 (GRCh38)
Gene constraint: LOEUF 0.318 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 52.20
Residue 259: the 'disordered' region

Full AFF3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

AFF3 p.Ala233Thr Pathogenic ★★ ⚠ same condition
AFF3 p.Ile1147Asn Uncertain significance ★★ ⚠ same condition
AFF3 p.Leu370Phe Uncertain significance ★★ ⚠ same condition
AFF3 p.Pro321Leu Uncertain significance ★★ ⚠ same condition
AFF3 p.Ser222Thr Uncertain significance ★★ ⚠ same condition
AFF3 p.Thr950Met Uncertain significance ★★ ⚠ same condition
AFF3 p.Ala1100Val Uncertain significance ★ ⚠ same condition
AFF3 p.Ala1103Thr 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/aff3-p-val259met (accessed [today's date]).

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