Is CPSF1 p.Pro687Ser (c.2059C>T) pathogenic?

CPSF1 p.Pro687Ser (c.2059C>T) is classified Uncertain significance in CPSF1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-22). AlphaMissense: likely pathogenic (0.6438); Very rare (popmax 0.00167%, amr).

How common is CPSF1 p.Pro687Ser (c.2059C>T) in the general population?

CPSF1 p.Pro687Ser (c.2059C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about CPSF1 p.Pro687Ser (c.2059C>T)?

AlphaMissense predicts likely pathogenic (score 0.6438) — an in-silico prediction, not a clinical call.

CPSF1 p.Pro687Ser

c.2059C>T · VCV4838227

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6438 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6438	likely pathogenic
REVEL	0.156	moderately benign-leaning
SaProt	LLR -11.82	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 1,464 bp · p 0.00021 · regional, not allelic
Overall
CADD	23.4	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 0.00167% Admixed American · 1/59,844 alleles

Overall 0.000124% 2/1,609,298 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	59,844
European (non-Finnish)	8.48e-05%	1,179,065

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.Pro687Ser
Coding: c.2059C>T
MANE Select: NM_013291
Type: single nucleotide variant
Location: chr8:144397968 (GRCh38)
Gene constraint: LOEUF 0.74 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.97 · 13 PDB
Residue 687: a UniProt-annotated variant site (in myp27)

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-pro687ser (accessed [today's date]).

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