Is CPSF2 p.Leu364Ser (c.1091T>C) pathogenic?

CPSF2 p.Leu364Ser (c.1091T>C) is classified Uncertain significance in CPSF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-26). AlphaMissense: likely pathogenic (0.9481); Ultra-rare (popmax 0.0134%, amr).

How common is CPSF2 p.Leu364Ser (c.1091T>C) in the general population?

CPSF2 p.Leu364Ser (c.1091T>C) is ultra-rare (popmax 0.0134%, amr) (gnomAD).

What do computational predictors say about CPSF2 p.Leu364Ser (c.1091T>C)?

AlphaMissense predicts likely pathogenic (score 0.9481) — an in-silico prediction, not a clinical call.

CPSF2 p.Leu364Ser

c.1091T>C · rs527771956 · VCV2308893

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9481 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0134%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9481	likely pathogenic
REVEL	0.746	pathogenic-leaning
SaProt	LLR -14.09	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	Δ0.22	acceptor gain · deltas
Pangolin	Δ0.23	gain · loss 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 7.9	GERP 2.1, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 19 kb · p 1.5e-07 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0134% Admixed American · 8/59,830 alleles

Filtering AF 0.00663% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00484%

Overall 0.000558% 9/1,612,600 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0134%	7,479
South Asian	0.0011%	90,844

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.Leu364Ser
Coding: c.1091T>C
MANE Select: NM_017437
dbSNP: rs527771956
Type: single nucleotide variant
Location: chr14:92143245 (GRCh38)
Gene constraint: LOEUF 0.651 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.14 · 6 PDB
Residue 364: an α-helix

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-leu364ser (accessed [today's date]).

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