Is AFF2 p.Ser496Leu (c.1487C>T) pathogenic?

AFF2 p.Ser496Leu (c.1487C>T) is classified Uncertain significance in AFF2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-02-21). AlphaMissense: likely pathogenic (0.76); Very rare (popmax 0.000447%, nfe); Associated with Inborn genetic diseases.

What condition is associated with AFF2 p.Ser496Leu (c.1487C>T)?

AFF2 p.Ser496Leu (c.1487C>T) is associated with Inborn genetic diseases (ClinVar).

How common is AFF2 p.Ser496Leu (c.1487C>T) in the general population?

AFF2 p.Ser496Leu (c.1487C>T) is very rare (popmax 0.000447%, nfe) (gnomAD).

What do computational predictors say about AFF2 p.Ser496Leu (c.1487C>T)?

AlphaMissense predicts likely pathogenic (score 0.76) — an in-silico prediction, not a clinical call.

AFF2 p.Ser496Leu

c.1487C>T · rs2071997289 · VCV1307965

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.76 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000447%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.76	likely pathogenic
REVEL	0.53	indeterminate
SaProt	LLR -10.59	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.9, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 304 kb · p 0.17 · regional, not allelic
Overall
CADD	23.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000447% European (non-Finnish) · 4/894,948 alleles

Filtering AF 0.000105% ClinGen BA1/BS1 input FAF95, joint · FAF99 7.1e-05%

Overall 0.000331% 4/1,209,258 alleles · very rare

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: AFF2
Protein: p.Ser496Leu
Coding: c.1487C>T
MANE Select: NM_002025
dbSNP: rs2071997289
Type: single nucleotide variant
Location: chrX:148953669 (GRCh38)
Structure: AlphaFold pLDDT 49.27
Residue 496: the 'disordered' region

Full AFF2 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

AFF2 p.Ser496= Benign ★★ same residue
AFF2 p.Ala1197Thr Uncertain significance ★★ ⚠ same condition
AFF2 p.Arg1295Cys Uncertain significance ★★ ⚠ same condition
AFF2 p.Asp187Glu Uncertain significance ★★ ⚠ same condition
AFF2 p.Gln205Lys Uncertain significance ★★ ⚠ same condition
AFF2 p.Gly482Arg Uncertain significance ★★ ⚠ same condition
AFF2 p.Gly740Val Uncertain significance ★★ ⚠ same condition
AFF2 p.His1070Arg 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/aff2-p-ser496leu (accessed [today's date]).

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