Is AFF2 p.Pro689Ser (c.2065C>T) pathogenic?

AFF2 p.Pro689Ser (c.2065C>T) is classified Likely benign in AFF2 (ClinVar, Single submitter, 3 submitters; last evaluated 2024-10-17). AlphaMissense: likely benign (0.0608); Rare (popmax 0.109%, nfe).

How common is AFF2 p.Pro689Ser (c.2065C>T) in the general population?

AFF2 p.Pro689Ser (c.2065C>T) is rare (popmax 0.109%, nfe) (gnomAD).

What do computational predictors say about AFF2 p.Pro689Ser (c.2065C>T)?

AlphaMissense predicts likely benign (score 0.0608) — an in-silico prediction, not a clinical call.

AFF2 p.Pro689Ser

c.2065C>T · rs140525796 · VCV1206189

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0608 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.109%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0608	likely benign
REVEL	0.032	moderately 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 0.26	GERP -1.2, phastCons 0.008
Regional constraint	o/e 0.94	unconstrained · MANE · 304 kb · p 0.17 · regional, not allelic
Overall
CADD	1.349	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 0.109% European (non-Finnish) · 978/894,792 alleles

Filtering AF 0.104% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.101%

Overall 0.152% 1,838/1,208,160 alleles · rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	1.57%	64
Ashkenazi Jewishnot grpmax-eligible	0.295%	339
European (non-Finnish)grpmax	0.109%	915
Remaining individualsnot grpmax-eligible	0.107%	933
Admixed American	0.022%	4,554
African / African-American	0.0141%	7,074

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro689Ser
Coding: c.2065C>T
MANE Select: NM_002025
dbSNP: rs140525796
Type: single nucleotide variant
Location: chrX:148956110 (GRCh38)
Structure: AlphaFold pLDDT 49.27
Residue 689: the 'disordered' region

Full AFF2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

AFF2 c.3267+5G>C Uncertain significance ★★ same type
AFF2 p.Ala1197Thr Uncertain significance ★★ ⚠ same type
AFF2 p.Ala171Pro Uncertain significance ★★ ⚠ same type
AFF2 p.Arg1238Cys Uncertain significance ★★ ⚠ same type
AFF2 p.Arg1295Cys Uncertain significance ★★ ⚠ same type
AFF2 p.Arg670His Uncertain significance ★★ ⚠ same type
AFF2 p.Asn77Ile Uncertain significance ★★ ⚠ same type
AFF2 p.Asp187Glu 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/aff2-p-pro689ser (accessed [today's date]).

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