Is AFF2 p.Ser421Leu (c.1262C>T) pathogenic?

AFF2 p.Ser421Leu (c.1262C>T) is classified Uncertain significance in AFF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-22). AlphaMissense: likely pathogenic (0.5972); Very rare (popmax 0.00352%, afr).

How common is AFF2 p.Ser421Leu (c.1262C>T) in the general population?

AFF2 p.Ser421Leu (c.1262C>T) is very rare (popmax 0.00352%, afr) (gnomAD).

What do computational predictors say about AFF2 p.Ser421Leu (c.1262C>T)?

AlphaMissense predicts likely pathogenic (score 0.5972) — an in-silico prediction, not a clinical call.

AFF2 p.Ser421Leu

c.1262C>T · VCV3369367

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5972 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00352%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.5972	likely pathogenic
REVEL	0.186	benign-leaning
SaProt	LLR -8.37	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.26 · evaluated, not missing
Constraint at this position
Conservation	phyloP -0.87	GERP -1.9, phastCons 0.001
Regional constraint	o/e 0.94	unconstrained · MANE · 304 kb · p 0.17 · regional, not allelic
Overall
CADD	16.6	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 0.00352% African / African-American · 2/56,841 alleles

Filtering AF 0.000584% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000218%

Overall 0.000747% 9/1,205,178 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00352%	28,420
Remaining individualsnot grpmax-eligible	0.00211%	47,465
European (non-Finnish)	0.000673%	148,695

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.Ser421Leu
Coding: c.1262C>T
MANE Select: NM_002025
Type: single nucleotide variant
Location: chrX:148843433 (GRCh38)
Structure: AlphaFold pLDDT 49.27

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-ser421leu (accessed [today's date]).

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