Is CPSF1 p.Ser674= (c.2022C>G) pathogenic?

CPSF1 p.Ser674= (c.2022C>G) is classified Benign in CPSF1 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2020-11-20). Rare (popmax 0.491%, afr); Associated with CPSF1-related disorder.

What condition is associated with CPSF1 p.Ser674= (c.2022C>G)?

CPSF1 p.Ser674= (c.2022C>G) is associated with CPSF1-related disorder (ClinVar).

How common is CPSF1 p.Ser674= (c.2022C>G) in the general population?

CPSF1 p.Ser674= (c.2022C>G) is rare (popmax 0.491%, afr) (gnomAD).

CPSF1 p.Ser674=

c.2022C>G · rs148200138 · VCV3051989

Benign No assertion criteria

Classification

Benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

rare (popmax 0.491%, afr)

Conditions

CPSF1-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.46	donor gain · deltas
Constraint at this position
Conservation	phyloP -9.3	GERP -3.8
Overall
CADD	9.963	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.491% African / African-American · 368/74,964 alleles

Filtering AF 0.449% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.433%

Overall 0.0293% 472/1,611,892 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.491%	204
Middle Eastern	0.314%	319
Admixed American	0.03%	3,331
Remaining individualsnot grpmax-eligible	0.0272%	3,674
South Asian	0.0044%	22,753
European (non-Finnish)	0.0039%	25,645

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.Ser674=
Coding: c.2022C>G
MANE Select: NM_013291
dbSNP: rs148200138
Type: single nucleotide variant
Location: chr8:144398005 (GRCh38)
Gene constraint: LOEUF 0.74 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.97 · 13 PDB
Residue 674: a UniProt-annotated variant site (in myp27)

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.Pro1043Ser 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.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-ser674 (accessed [today's date]).

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