Is CPSF1 p.Arg985Cys (c.2953C>T) pathogenic?

CPSF1 p.Arg985Cys (c.2953C>T) is classified Uncertain significance in CPSF1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-16). AlphaMissense: ambiguous (0.348); Ultra-rare (popmax 0.0295%, amr).

How common is CPSF1 p.Arg985Cys (c.2953C>T) in the general population?

CPSF1 p.Arg985Cys (c.2953C>T) is ultra-rare (popmax 0.0295%, amr) (gnomAD).

What do computational predictors say about CPSF1 p.Arg985Cys (c.2953C>T)?

AlphaMissense predicts ambiguous (score 0.348) — an in-silico prediction, not a clinical call.

CPSF1 p.Arg985Cys

c.2953C>T · rs374513752 · VCV2455617

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.348 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0295%, amr)

Computational evidence

Protein change
AlphaMissense	0.348	ambiguous
REVEL	0.613	indeterminate
SaProt	LLR -6.52	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.3	GERP 1.6, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 2,917 bp · p 0.99 · regional, not allelic
Overall
CADD	28.5	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 0.0295% Admixed American · 16/54,184 alleles

Filtering AF 0.0185% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0151%

Overall 0.00951% 151/1,587,996 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0295%	3,387
European (non-Finnish)	0.0109%	9,213
Remaining individualsnot grpmax-eligible	0.00487%	20,540
African / African-American	0.00401%	24,941
Ashkenazi Jewishnot grpmax-eligible	0.00344%	29,076
East Asian	0.00227%	44,098

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.Arg985Cys
Coding: c.2953C>T
MANE Select: NM_013291
dbSNP: rs374513752
Type: single nucleotide variant
Location: chr8:144396374 (GRCh38)
Gene constraint: LOEUF 0.74 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.97 · 13 PDB
Residue 985: 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.Arg985His Uncertain significance ★ ⚠ same residue
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

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-arg985cys (accessed [today's date]).

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