Is CPSF6 p.Arg118Trp (c.352C>T) pathogenic?

CPSF6 p.Arg118Trp (c.352C>T) is classified Uncertain significance in CPSF6 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-28). AlphaMissense: likely pathogenic (0.9987); Very rare (popmax 8.57e-05%, nfe).

How common is CPSF6 p.Arg118Trp (c.352C>T) in the general population?

CPSF6 p.Arg118Trp (c.352C>T) is very rare (popmax 8.57e-05%, nfe) (gnomAD).

What do computational predictors say about CPSF6 p.Arg118Trp (c.352C>T)?

AlphaMissense predicts likely pathogenic (score 0.9987) — an in-silico prediction, not a clinical call.

CPSF6 p.Arg118Trp

c.352C>T · rs1227467387 · VCV2267806

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9987 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.57e-05%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9987	likely pathogenic · top 8% in CPSF6
REVEL	0.284	benign-leaning
SaProt	LLR -16.22	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 4	GERP -0.8, phastCons 1
Regional constraint	o/e 0.58	unconstrained · MANE · 18 kb · p 5.3e-10 · regional, not allelic
Overall
CADD	25.8	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 8.57e-05% European (non-Finnish) · 1/1,166,620 alleles

Overall 0.000126% 2/1,591,456 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00343%	29,190
European (non-Finnish)grpmax	8.57e-05%	1,166,620

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg118Trp
Coding: c.352C>T
MANE Select: NM_007007
dbSNP: rs1227467387
Type: single nucleotide variant
Location: chr12:69253132 (GRCh38)
Gene constraint: LOEUF 0.306 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 65.11 · 17 PDB
Residue 118: the rrm domain; the 'necessary for interaction with nxf1' region; the 'necessary for interaction with nudt21/cpsf5' region; the 'necessary for nuclear paraspeckles localization' region; a turn

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

Similar variants

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
CPSF6 p.Asp54Ala 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-arg118trp (accessed [today's date]).

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