Is CPSF7 p.Leu144Phe (c.430C>T) pathogenic?

CPSF7 p.Leu144Phe (c.430C>T) is classified Uncertain significance in CPSF7 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-19). AlphaMissense: likely benign (0.2162); Very rare (popmax 0.000678%, nfe).

How common is CPSF7 p.Leu144Phe (c.430C>T) in the general population?

CPSF7 p.Leu144Phe (c.430C>T) is very rare (popmax 0.000678%, nfe) (gnomAD).

What do computational predictors say about CPSF7 p.Leu144Phe (c.430C>T)?

AlphaMissense predicts likely benign (score 0.2162) — an in-silico prediction, not a clinical call.

CPSF7 p.Leu144Phe

c.430C>T · VCV3269281

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2162 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000678%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2162	likely benign
REVEL	0.192	benign-leaning
SaProt	LLR -7.86	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 10	GERP 1.8, phastCons 1
Regional constraint	o/e 0.73	unconstrained · MANE · 18 kb · p 2.7e-11 · regional, not allelic
Overall
CADD	24.3	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 0.000678% European (non-Finnish) · 8/1,179,962 alleles

Filtering AF 0.000292% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.000496% 8/1,613,984 alleles · very rare

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: CPSF7
Protein: p.Leu144Phe
Coding: c.430C>T
MANE Select: NM_001142565
Type: single nucleotide variant
Location: chr11:61420042 (GRCh38)
Gene constraint: LOEUF 0.13 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 65.55 · 1 PDB
Residue 144: the rrm domain; an α-helix

Full CPSF7 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CPSF7 c.-15C>T Uncertain significance ★ same type
CPSF7 c.-21C>G Uncertain significance ★ same type
CPSF7 c.-56+117C>T Uncertain significance ★ same type
CPSF7 c.-56+123C>G Uncertain significance ★ same type
CPSF7 c.-56+124C>T Uncertain significance ★ same type
CPSF7 c.-56+133G>C Uncertain significance ★ same type
CPSF7 c.-56+138G>C Uncertain significance ★ same type
CPSF7 c.-56+150C>T 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/cpsf7-p-leu144phe (accessed [today's date]).

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