Is AFF2 p.Phe48Leu (c.142T>C) pathogenic?

AFF2 p.Phe48Leu (c.142T>C) is classified Uncertain significance in AFF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-28). AlphaMissense: likely pathogenic (0.9836); Very rare (popmax 0.000113%, nfe).

How common is AFF2 p.Phe48Leu (c.142T>C) in the general population?

AFF2 p.Phe48Leu (c.142T>C) is very rare (popmax 0.000113%, nfe) (gnomAD).

What do computational predictors say about AFF2 p.Phe48Leu (c.142T>C)?

AlphaMissense predicts likely pathogenic (score 0.9836) — an in-silico prediction, not a clinical call.

AFF2 p.Phe48Leu

c.142T>C · VCV3360601

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9836 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000113%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9836	likely pathogenic · top 8% in AFF2
REVEL	0.48	indeterminate
SaProt	LLR -6.75	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 2.7, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 161 kb · p 0.93 · regional, not allelic
Overall
CADD	25.7	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 0.000113% European (non-Finnish) · 1/887,972 alleles

Overall 9.18e-05% 1/1,089,058 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.Phe48Leu
Coding: c.142T>C
MANE Select: NM_002025
Type: single nucleotide variant
Location: chrX:148652093 (GRCh38)
Structure: AlphaFold pLDDT 49.27

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

Similar variants

AFF2 p.Phe48Tyr Uncertain significance ★ ⚠ same residue
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

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-phe48leu (accessed [today's date]).

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