Is CPSF1 p.Glu58Asp (c.174G>C) pathogenic?

CPSF1 p.Glu58Asp (c.174G>C) is classified Uncertain significance in CPSF1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-08). AlphaMissense: likely benign (0.0672); Rare (popmax 0.495%, amr).

How common is CPSF1 p.Glu58Asp (c.174G>C) in the general population?

CPSF1 p.Glu58Asp (c.174G>C) is rare (popmax 0.495%, amr) (gnomAD).

What do computational predictors say about CPSF1 p.Glu58Asp (c.174G>C)?

AlphaMissense predicts likely benign (score 0.0672) — an in-silico prediction, not a clinical call.

CPSF1 p.Glu58Asp

c.174G>C · VCV4656233

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0672 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.495%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0672	likely benign
REVEL	0.036	moderately benign-leaning
SaProt	LLR -6.75	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>T here scores Δ0.75 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.096	GERP -0.91, phastCons 0.93
Regional constraint	o/e 1.07	unconstrained · MANE · 7,681 bp · p 0.45 · regional, not allelic
Overall
CADD	8.437	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 0.495% Admixed American · 297/59,964 alleles

Filtering AF 0.449% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.431%

Overall 0.138% 2,223/1,613,546 alleles · rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.495%	202
Remaining individualsnot grpmax-eligible	0.152%	657
European (non-Finnish)	0.15%	668
Ashkenazi Jewishnot grpmax-eligible	0.105%	955
African / African-American	0.04%	2,502
Middle Eastern	0.0165%	6,058
Finnishnot grpmax-eligible	0.00313%	31,926
South Asian	0.0011%	91,002

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.Glu58Asp
Coding: c.174G>C
MANE Select: NM_013291
Type: single nucleotide variant
Location: chr8:144401562 (GRCh38)
Gene constraint: LOEUF 0.74 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.97 · 13 PDB
Residue 58: 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.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
CPSF1 c.1119+2T>G 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/cpsf1-p-glu58asp (accessed [today's date]).

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