Is CPSF6 p.Pro288Ser (c.862C>T) pathogenic?

CPSF6 p.Pro288Ser (c.862C>T) is classified Uncertain significance in CPSF6 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-17). AlphaMissense: likely benign (0.068); Very rare (popmax 8.47e-05%, nfe).

How common is CPSF6 p.Pro288Ser (c.862C>T) in the general population?

CPSF6 p.Pro288Ser (c.862C>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about CPSF6 p.Pro288Ser (c.862C>T)?

AlphaMissense predicts likely benign (score 0.068) — an in-silico prediction, not a clinical call.

CPSF6 p.Pro288Ser

c.862C>T · rs2498989776 · VCV3076903

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.068 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.068	likely benign
REVEL	0.309	indeterminate
SaProt	LLR -10.72	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.8, phastCons 1
Regional constraint	o/e 0.71	unconstrained · MANE · 1,670 bp · p 7.8e-07 · regional, not allelic
Overall
CADD	22.6	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 8.47e-05% European (non-Finnish) · 1/1,180,000 alleles

Overall 6.84e-05% 1/1,461,888 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: CPSF6
Protein: p.Pro288Ser
Coding: c.862C>T
MANE Select: NM_007007
dbSNP: rs2498989776
Type: single nucleotide variant
Location: chr12:69258757 (GRCh38)
Gene constraint: LOEUF 0.306 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 65.11 · 17 PDB
Residue 288: the 'disordered' region; an α-helix

Full CPSF6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CPSF6 p.Arg118Trp Uncertain significance ★ ⚠ same type
CPSF6 p.Arg206His Uncertain significance ★ ⚠ same type
CPSF6 p.Arg272Cys Uncertain significance ★ ⚠ same type
CPSF6 p.Arg326His Uncertain significance ★ ⚠ same type
CPSF6 p.Arg542His Uncertain significance ★ ⚠ same type
CPSF6 p.Arg546Cys Uncertain significance ★ ⚠ same type
CPSF6 p.Asn19Ser Uncertain significance ★ ⚠ same type
CPSF6 p.Asp518Glu 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/cpsf6-p-pro288ser (accessed [today's date]).

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