Is AFF4 p.Ser1035Tyr (c.3104C>A) pathogenic?

AFF4 p.Ser1035Tyr (c.3104C>A) is classified Uncertain significance in AFF4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-01). AlphaMissense: ambiguous (0.5587); Very rare (popmax 8.54e-05%, nfe).

How common is AFF4 p.Ser1035Tyr (c.3104C>A) in the general population?

AFF4 p.Ser1035Tyr (c.3104C>A) is very rare (popmax 8.54e-05%, nfe) (gnomAD).

What do computational predictors say about AFF4 p.Ser1035Tyr (c.3104C>A)?

AlphaMissense predicts ambiguous (score 0.5587) — an in-silico prediction, not a clinical call.

AFF4 p.Ser1035Tyr

c.3104C>A · rs2532434622 · VCV3239369

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5587 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.54e-05%, nfe)

Computational evidence

Protein change
AlphaMissense	0.5587	ambiguous
REVEL	0.48	indeterminate
SaProt	LLR -8.32	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 5.7, phastCons 1
Regional constraint	o/e 0.59	unconstrained · MANE · 8,017 bp · p 1.3e-12 · regional, not allelic
Overall
CADD	28.5	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 8.54e-05% European (non-Finnish) · 1/1,170,276 alleles

Overall 6.94e-05% 1/1,440,706 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: AFF4
Protein: p.Ser1035Tyr
Coding: c.3104C>A
MANE Select: NM_014423
dbSNP: rs2532434622
Type: single nucleotide variant
Location: chr5:132885115 (GRCh38)
Gene constraint: LOEUF 0.114 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 54.62 · 9 PDB
Residue 1035: the 'disordered' region

Full AFF4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

AFF4 p.Arg258Trp Pathogenic/Likely pathogenic ★★ same type
AFF4 p.Met260Val Likely pathogenic ★★ ⚠ same type
AFF4 p.Pro253Leu Pathogenic/Likely pathogenic ★★ same type
AFF4 p.Thr254Ser Pathogenic/Likely pathogenic ★★ ⚠ same type
AFF4 c.1133+3A>G Uncertain significance ★★ same type
AFF4 p.Ala114Thr Uncertain significance ★★ ⚠ same type
AFF4 p.Ala114Val Uncertain significance ★★ ⚠ same type
AFF4 p.Ala27Thr Uncertain significance ★★ ⚠ same type

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-ser1035tyr (accessed [today's date]).

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