Is AFF2 p.Ser1068Trp (c.3203C>G) pathogenic?

AFF2 p.Ser1068Trp (c.3203C>G) is classified Likely pathogenic in AFF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-03-02). AlphaMissense: ambiguous (0.4775); Very rare (popmax 0.000112%, nfe); Associated with primary ovarian failure.

What condition is associated with AFF2 p.Ser1068Trp (c.3203C>G)?

AFF2 p.Ser1068Trp (c.3203C>G) is associated with primary ovarian failure (ClinVar).

How common is AFF2 p.Ser1068Trp (c.3203C>G) in the general population?

AFF2 p.Ser1068Trp (c.3203C>G) is very rare (popmax 0.000112%, nfe) (gnomAD).

What do computational predictors say about AFF2 p.Ser1068Trp (c.3203C>G)?

AlphaMissense predicts ambiguous (score 0.4775) — an in-silico prediction, not a clinical call.

AFF2 p.Ser1068Trp

c.3203C>G · rs188208167 · VCV929787

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4775 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000112%, nfe)

Conditions

primary ovarian failure

Computational evidence

Protein change
AlphaMissense	0.4775	ambiguous
REVEL	0.359	indeterminate
SaProt	LLR -13.47	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.7	GERP 1.5, phastCons 1
Regional constraint	o/e 0.48	unconstrained · MANE · 14 kb · p 2.1e-08 · regional, not allelic
Overall
CADD	26.6	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 0.000112% European (non-Finnish) · 1/894,409 alleles

Overall 9.13e-05% 1/1,095,486 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: AFF2
Protein: p.Ser1068Trp
Coding: c.3203C>G
MANE Select: NM_002025
dbSNP: rs188208167
Type: single nucleotide variant
Location: chrX:148967079 (GRCh38)
Structure: AlphaFold pLDDT 49.27

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

Disease context

primary ovarian failure — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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-ser1068trp (accessed [today's date]).

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