Is CPSF1 p.Arg985His (c.2954G>A) pathogenic?

CPSF1 p.Arg985His (c.2954G>A) is classified Uncertain significance in CPSF1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-13). AlphaMissense: likely benign (0.1533); Ultra-rare (popmax 0.0363%, eas).

How common is CPSF1 p.Arg985His (c.2954G>A) in the general population?

CPSF1 p.Arg985His (c.2954G>A) is ultra-rare (popmax 0.0363%, eas) (gnomAD).

What do computational predictors say about CPSF1 p.Arg985His (c.2954G>A)?

AlphaMissense predicts likely benign (score 0.1533) — an in-silico prediction, not a clinical call.

CPSF1 p.Arg985His

c.2954G>A · rs370174395 · VCV2409501

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1533 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0363%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1533	likely benign
REVEL	0.269	benign-leaning
SaProt	LLR -3.86	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.7	GERP -2, phastCons 0.91
Regional constraint	o/e 1.00	unconstrained · MANE · 2,917 bp · p 0.99 · regional, not allelic
Overall
CADD	21.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0363% East Asian · 16/44,112 alleles

Filtering AF 0.0227% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0185%

Overall 0.00705% 112/1,587,808 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0363%	2,757
Admixed American	0.00924%	10,826
Remaining individualsnot grpmax-eligible	0.00812%	12,319
European (non-Finnish)	0.00701%	14,270
South Asian	0.00343%	29,195
African / African-American	0.00134%	74,672

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.Arg985His
Coding: c.2954G>A
MANE Select: NM_013291
dbSNP: rs370174395
Type: single nucleotide variant
Location: chr8:144396373 (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.Arg985Cys 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-arg985his (accessed [today's date]).

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