Is CPSF7 p.Ile366Leu (c.1096A>C) pathogenic?

CPSF7 p.Ile366Leu (c.1096A>C) is classified Uncertain significance in CPSF7 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-25). AlphaMissense: likely pathogenic (0.6686); Very rare (popmax 0.00167%, amr).

How common is CPSF7 p.Ile366Leu (c.1096A>C) in the general population?

CPSF7 p.Ile366Leu (c.1096A>C) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about CPSF7 p.Ile366Leu (c.1096A>C)?

AlphaMissense predicts likely pathogenic (score 0.6686) — an in-silico prediction, not a clinical call.

CPSF7 p.Ile366Leu

c.1096A>C · VCV4233583

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6686 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.6686	likely pathogenic
REVEL	0.543	indeterminate
SaProt	LLR -10.34	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.5, phastCons 1
Regional constraint	o/e 0.73	unconstrained · MANE · 18 kb · p 2.7e-11 · regional, not allelic
Overall
CADD	25.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM I375L vs ClinVar I366L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/60,016 alleles

Overall 6.84e-05% 1/1,461,878 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: CPSF7
Protein: p.Ile366Leu
Coding: c.1096A>C
MANE Select: NM_001142565
Type: single nucleotide variant
Location: chr11:61411899 (GRCh38)
Gene constraint: LOEUF 0.13 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 65.55 · 1 PDB

Full CPSF7 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CPSF7 c.-15C>T Uncertain significance ★ same type
CPSF7 c.-21C>G Uncertain significance ★ same type
CPSF7 c.-56+117C>T Uncertain significance ★ same type
CPSF7 c.-56+123C>G Uncertain significance ★ same type
CPSF7 c.-56+124C>T Uncertain significance ★ same type
CPSF7 c.-56+133G>C Uncertain significance ★ same type
CPSF7 c.-56+138G>C Uncertain significance ★ same type
CPSF7 c.-56+150C>T 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/cpsf7-p-ile366leu (accessed [today's date]).

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