Is AFF2 p.Pro166Ser (c.496C>T) pathogenic?

AFF2 p.Pro166Ser (c.496C>T) is classified Benign/Likely benign in AFF2 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2024-11-01). AlphaMissense: likely benign (0.0588); Rare (popmax 0.161%, nfe).

How common is AFF2 p.Pro166Ser (c.496C>T) in the general population?

AFF2 p.Pro166Ser (c.496C>T) is rare (popmax 0.161%, nfe) (gnomAD).

What do computational predictors say about AFF2 p.Pro166Ser (c.496C>T)?

AlphaMissense predicts likely benign (score 0.0588) — an in-silico prediction, not a clinical call.

AFF2 p.Pro166Ser

c.496C>T · rs150996735 · VCV166657

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.0588 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.161%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0588	likely benign
REVEL	0.084	moderately benign-leaning
SaProt	LLR -5.39	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 -0.48	GERP -4.6
Regional constraint	o/e 1.01	unconstrained · MANE · 161 kb · p 0.93 · regional, not allelic
Overall
CADD	0.242	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 0.161% European (non-Finnish) · 1,438/894,783 alleles

Filtering AF 0.154% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.151%

Overall 0.132% 1,602/1,209,320 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.161%	622
Ashkenazi Jewishnot grpmax-eligible	0.127%	787
Remaining individualsnot grpmax-eligible	0.12%	835
Middle Eastern	0.0689%	1,450
Admixed American	0.0678%	1,475
South Asian	0.0564%	1,774
African / African-American	0.0158%	6,344
Finnishnot grpmax-eligible	0.00859%	11,642

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.Pro166Ser
Coding: c.496C>T
MANE Select: NM_002025
dbSNP: rs150996735
Type: single nucleotide variant
Location: chrX:148662223 (GRCh38)
Structure: AlphaFold pLDDT 49.27
Residue 166: 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-pro166ser (accessed [today's date]).

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