Is CPSF2 p.Arg534Gln (c.1601G>A) pathogenic?

CPSF2 p.Arg534Gln (c.1601G>A) is classified Uncertain significance in CPSF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-27). AlphaMissense: likely benign (0.1281); Very rare (popmax 0.00446%, eas).

How common is CPSF2 p.Arg534Gln (c.1601G>A) in the general population?

CPSF2 p.Arg534Gln (c.1601G>A) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about CPSF2 p.Arg534Gln (c.1601G>A)?

AlphaMissense predicts likely benign (score 0.1281) — an in-silico prediction, not a clinical call.

CPSF2 p.Arg534Gln

c.1601G>A · rs755284631 · VCV2397038

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1281 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1281	likely benign
REVEL	0.697	pathogenic-leaning
SaProt	LLR -9.04	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.4, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 19 kb · p 1.5e-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 0.00446% East Asian · 2/44,876 alleles

Filtering AF 0.00165% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00142%

Overall 0.00205% 33/1,612,034 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,438
Remaining individualsnot grpmax-eligible	0.0032%	31,204
European (non-Finnish)	0.00238%	42,089
South Asian	0.0011%	91,028

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: CPSF2
Protein: p.Arg534Gln
Coding: c.1601G>A
MANE Select: NM_017437
dbSNP: rs755284631
Type: single nucleotide variant
Location: chr14:92157664 (GRCh38)
Gene constraint: LOEUF 0.651 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.14 · 6 PDB
Residue 534: a β-strand

Full CPSF2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CPSF2 p.Ala267Val Uncertain significance ★ ⚠ same type
CPSF2 p.Arg105Gln Uncertain significance ★ ⚠ same type
CPSF2 p.Arg366Cys Uncertain significance ★ ⚠ same type
CPSF2 p.Arg366His Uncertain significance ★ ⚠ same type
CPSF2 p.Arg449His Uncertain significance ★ ⚠ same type
CPSF2 p.Arg579His Uncertain significance ★ ⚠ same type
CPSF2 p.Arg730Gln Uncertain significance ★ ⚠ same type
CPSF2 p.Arg751His 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/cpsf2-p-arg534gln (accessed [today's date]).

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