Is AFF1 p.Pro249Ser (c.745C>T) pathogenic?

AFF1 p.Pro249Ser (c.745C>T) is classified Uncertain significance in AFF1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-05). AlphaMissense: likely benign (0.0774); Ultra-rare (popmax 0.0493%, mid).

How common is AFF1 p.Pro249Ser (c.745C>T) in the general population?

AFF1 p.Pro249Ser (c.745C>T) is ultra-rare (popmax 0.0493%, mid) (gnomAD).

What do computational predictors say about AFF1 p.Pro249Ser (c.745C>T)?

AlphaMissense predicts likely benign (score 0.0774) — an in-silico prediction, not a clinical call.

AFF1 p.Pro249Ser

c.745C>T · VCV3503623

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0774 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0493%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0774	likely benign
REVEL	0.191	benign-leaning
SaProt	LLR -5.71	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 1.4	GERP 0.29, phastCons 0.009
Regional constraint	o/e 1.00	unconstrained · MANE · 99 kb · p 0.92 · regional, not allelic
Overall
CADD	14.82	PHRED · no single calibrated threshold — expert panels disagree

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

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P242S vs ClinVar P249S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0493% Middle Eastern · 3/6,084 alleles

Filtering AF 0.0134% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00905%

Overall 0.00204% 33/1,613,968 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0493%	2,028
African / African-American	0.0187%	5,347
Remaining individualsnot grpmax-eligible	0.008%	12,497
South Asian	0.00439%	22,770
Admixed American	0.00333%	29,999
European (non-Finnish)	0.000424%	236,007

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.Pro249Ser
Coding: c.745C>T
MANE Select: NM_001166693
Type: single nucleotide variant
Location: chr4:87047280 (GRCh38)
Gene constraint: LOEUF 0.49 · pLI 0.95 (gnomAD)
Structure: AlphaFold pLDDT 53.06 · 1 PDB
Residue 249: the 'disordered' region

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

Similar variants

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
AFF1 p.Ala1047Val Uncertain significance ★ ⚠ same type
AFF1 p.Ala1103Thr 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/aff1-p-pro249ser (accessed [today's date]).

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