Is AFF4 p.Pro342Leu (c.1025C>T) pathogenic?

AFF4 p.Pro342Leu (c.1025C>T) is classified Uncertain significance in AFF4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-01). AlphaMissense: ambiguous (0.4246); Absent from gnomAD v4.1.

How common is AFF4 p.Pro342Leu (c.1025C>T) in the general population?

AFF4 p.Pro342Leu (c.1025C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about AFF4 p.Pro342Leu (c.1025C>T)?

AlphaMissense predicts ambiguous (score 0.4246) — an in-silico prediction, not a clinical call.

AFF4 p.Pro342Leu

c.1025C>T · rs2532556875 · VCV2662450

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4246 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4246	ambiguous
REVEL	0.644	pathogenic-leaning
SaProt	LLR -7.20	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 6, phastCons 1
Regional constraint	o/e 0.75	unconstrained · MANE · 36 kb · p 0.00057 · regional, not allelic
Overall
CADD	29.7	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: AFF4
Protein: p.Pro342Leu
Coding: c.1025C>T
MANE Select: NM_014423
dbSNP: rs2532556875
Type: single nucleotide variant
Location: chr5:132927146 (GRCh38)
Gene constraint: LOEUF 0.114 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 54.62 · 9 PDB
Residue 342: the 'disordered' region

Full AFF4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

AFF4 p.Arg258Trp Pathogenic/Likely pathogenic ★★ same type
AFF4 p.Met260Val Likely pathogenic ★★ ⚠ same type
AFF4 p.Pro253Leu Pathogenic/Likely pathogenic ★★ same type
AFF4 p.Thr254Ser Pathogenic/Likely pathogenic ★★ ⚠ same type
AFF4 c.1133+3A>G Uncertain significance ★★ same type
AFF4 p.Ala114Thr Uncertain significance ★★ ⚠ same type
AFF4 p.Ala114Val Uncertain significance ★★ ⚠ same type
AFF4 p.Ala27Thr 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/aff4-p-pro342leu (accessed [today's date]).

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