Is CPSF1 p.Pro1315Leu (c.3944C>T) pathogenic?

CPSF1 p.Pro1315Leu (c.3944C>T) is classified Uncertain significance in CPSF1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-08). AlphaMissense: likely benign (0.2093); Ultra-rare (popmax 0.0176%, sas).

How common is CPSF1 p.Pro1315Leu (c.3944C>T) in the general population?

CPSF1 p.Pro1315Leu (c.3944C>T) is ultra-rare (popmax 0.0176%, sas) (gnomAD).

What do computational predictors say about CPSF1 p.Pro1315Leu (c.3944C>T)?

AlphaMissense predicts likely benign (score 0.2093) — an in-silico prediction, not a clinical call.

CPSF1 p.Pro1315Leu

c.3944C>T · VCV4233550

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2093 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0176%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2093	likely benign
REVEL	0.18	moderately benign-leaning
SaProt	LLR -5.57	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.6	GERP 0.8, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 1,165 bp · p 0.4 · regional, not allelic
Overall
CADD	23.7	PHRED · no single calibrated threshold — expert panels disagree

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

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0176% South Asian · 16/91,072 alleles

Filtering AF 0.011% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00898%

Overall 0.00254% 41/1,613,500 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0176%	5,692
Middle Eastern	0.0164%	6,084
African / African-American	0.00801%	12,483
Remaining individualsnot grpmax-eligible	0.0048%	20,822
East Asian	0.00223%	44,882
European (non-Finnish)	0.00119%	84,279

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: CPSF1
Protein: p.Pro1315Leu
Coding: c.3944C>T
MANE Select: NM_013291
Type: single nucleotide variant
Location: chr8:144393954 (GRCh38)
Gene constraint: LOEUF 0.74 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.97 · 13 PDB
Residue 1315: a UniProt-annotated variant site (in myp27); a β-strand

Full CPSF1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CPSF1 p.Ala1319Thr Uncertain significance ★★ ⚠ same type
CPSF1 p.Thr561Ile Uncertain significance ★★ ⚠ same type
CPSF1 p.Gly722= Likely benign ★★ same type
CPSF1 p.Leu1360= Likely benign ★★ same type
CPSF1 p.Pro438= Likely benign ★★ same type
CPSF1 p.Pro654= Likely benign ★★ same type
CPSF1 c.539+1G>A Likely pathogenic ★ same type
CPSF1 c.1119+2T>G 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/cpsf1-p-pro1315leu (accessed [today's date]).

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