Is CPSF1 p.Pro1043Ser (c.3127C>T) pathogenic?

CPSF1 p.Pro1043Ser (c.3127C>T) is classified Uncertain significance in CPSF1 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-03-29). AlphaMissense: likely benign (0.0744); Very rare (popmax 0.00801%, afr); Associated with CPSF1-related disorder.

What condition is associated with CPSF1 p.Pro1043Ser (c.3127C>T)?

CPSF1 p.Pro1043Ser (c.3127C>T) is associated with CPSF1-related disorder (ClinVar).

How common is CPSF1 p.Pro1043Ser (c.3127C>T) in the general population?

CPSF1 p.Pro1043Ser (c.3127C>T) is very rare (popmax 0.00801%, afr) (gnomAD).

What do computational predictors say about CPSF1 p.Pro1043Ser (c.3127C>T)?

AlphaMissense predicts likely benign (score 0.0744) — an in-silico prediction, not a clinical call.

CPSF1 p.Pro1043Ser

c.3127C>T · VCV3348172

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0744 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00801%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

CPSF1-related disorder

Computational evidence

Protein change
AlphaMissense	0.0744	likely benign
REVEL	0.216	benign-leaning
SaProt	LLR -7.21	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 4.3	GERP -0.88, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 2,917 bp · p 0.99 · regional, not allelic
Overall
CADD	14.18	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 0.00801% African / African-American · 6/74,902 alleles

Filtering AF 0.00347% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00229%

Overall 0.000372% 6/1,613,390 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: CPSF1
Protein: p.Pro1043Ser
Coding: c.3127C>T
MANE Select: NM_013291
Type: single nucleotide variant
Location: chr8:144395325 (GRCh38)
Gene constraint: LOEUF 0.74 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.97 · 13 PDB
Residue 1043: a UniProt-annotated variant site (in myp27); a β-strand

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

Disease context

CPSF1-related disorder

Similar variants

CPSF1 c.1119+2T>G Uncertain significance ★ same condition
CPSF1 p.Thr304Ala Uncertain significance ⚠ same condition
CPSF1 p.Thr397Met Uncertain significance ⚠ same condition
CPSF1 p.Ala918Thr Likely benign same condition
CPSF1 p.Ser674= Benign same condition
CPSF1 p.Thr606= Likely benign same condition
CPSF1 p.Asn991del Uncertain significance same condition
CPSF1 c.4146-7_4146-6del Likely benign same condition

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-pro1043ser (accessed [today's date]).

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