Is CPSF2 p.Met42Val (c.124A>G) pathogenic?

CPSF2 p.Met42Val (c.124A>G) is classified Uncertain significance in CPSF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-17). AlphaMissense: likely benign (0.0921); Ultra-rare (popmax 0.0917%, amr).

How common is CPSF2 p.Met42Val (c.124A>G) in the general population?

CPSF2 p.Met42Val (c.124A>G) is ultra-rare (popmax 0.0917%, amr) (gnomAD).

What do computational predictors say about CPSF2 p.Met42Val (c.124A>G)?

AlphaMissense predicts likely benign (score 0.0921) — an in-silico prediction, not a clinical call.

CPSF2 p.Met42Val

c.124A>G · rs761015090 · VCV2362422

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0921 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0917%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0921	likely benign
REVEL	0.213	benign-leaning
SaProt	LLR -9.46	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 3	GERP -1.3, phastCons 0.97
Regional constraint	o/e 0.56	unconstrained · MANE · 12 kb · p 1.9e-17 · regional, not allelic
Overall
CADD	14.2	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 0.0917% Admixed American · 53/57,794 alleles

Filtering AF 0.072% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0649%

Overall 0.00672% 108/1,606,182 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0917%	1,090
Remaining individualsnot grpmax-eligible	0.0161%	6,222
East Asian	0.00895%	11,173
European (non-Finnish)	0.00331%	30,199
African / African-American	0.00134%	74,482
South Asian	0.00113%	88,886

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.Met42Val
Coding: c.124A>G
MANE Select: NM_017437
dbSNP: rs761015090
Type: single nucleotide variant
Location: chr14:92131108 (GRCh38)
Gene constraint: LOEUF 0.651 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.14 · 6 PDB

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.Arg534Gln Uncertain significance ★ ⚠ same type
CPSF2 p.Arg579His Uncertain significance ★ ⚠ same type
CPSF2 p.Arg730Gln 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-met42val (accessed [today's date]).

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