Is AFF1 p.Ser1024Tyr (c.3071C>A) pathogenic?

AFF1 p.Ser1024Tyr (c.3071C>A) is classified Uncertain significance in AFF1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-22). AlphaMissense: likely benign (0.1285); Ultra-rare (popmax 0.0267%, eas).

How common is AFF1 p.Ser1024Tyr (c.3071C>A) in the general population?

AFF1 p.Ser1024Tyr (c.3071C>A) is ultra-rare (popmax 0.0267%, eas) (gnomAD).

What do computational predictors say about AFF1 p.Ser1024Tyr (c.3071C>A)?

AlphaMissense predicts likely benign (score 0.1285) — an in-silico prediction, not a clinical call.

AFF1 p.Ser1024Tyr

c.3071C>A · rs374537040 · VCV2621108

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1285 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0267%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1285	likely benign
REVEL	0.363	indeterminate
SaProt	LLR -10.43	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.3	GERP 2.4, phastCons 0.1
Regional constraint	o/e 0.91	unconstrained · MANE · 4,557 bp · p 0.14 · regional, not allelic
Overall
CADD	18.9	PHRED · no single calibrated threshold — expert panels disagree

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM S1017Y vs ClinVar S1024Y) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0267% East Asian · 12/44,888 alleles

Filtering AF 0.0154% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0121%

Overall 0.000821% 12/1,461,880 alleles · ultra-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: AFF1
Protein: p.Ser1024Tyr
Coding: c.3071C>A
MANE Select: NM_001166693
dbSNP: rs374537040
Type: single nucleotide variant
Location: chr4:87131189 (GRCh38)
Gene constraint: LOEUF 0.49 · pLI 0.95 (gnomAD)
Structure: AlphaFold pLDDT 53.06 · 1 PDB

Full AFF1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

AFF1 p.Ser1024Cys Uncertain significance ★ ⚠ same residue
AFF1 p.Ser1024Thr Uncertain significance ★ ⚠ same residue
AFF1 c.1191+8C>T Benign/Likely benign ★★ same type
AFF1 p.Ala40= Benign ★★ same type
AFF1 p.Pro393= Benign ★★ same type
AFF1 p.Ser627Cys Likely benign ★★ ⚠ same type
AFF1 p.Thr426= Likely benign ★★ same type
AFF1 p.Val711Ile Benign ★★ 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/aff1-p-ser1024tyr (accessed [today's date]).

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