Is CLIP4 p.Pro39Leu (c.116C>T) pathogenic?

CLIP4 p.Pro39Leu (c.116C>T) is classified Uncertain significance in CLIP4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-10). AlphaMissense: likely pathogenic (0.9379); Very rare (popmax 8.48e-05%, nfe).

How common is CLIP4 p.Pro39Leu (c.116C>T) in the general population?

CLIP4 p.Pro39Leu (c.116C>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about CLIP4 p.Pro39Leu (c.116C>T)?

AlphaMissense predicts likely pathogenic (score 0.9379) — an in-silico prediction, not a clinical call.

CLIP4 p.Pro39Leu

c.116C>T · VCV4229961

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9379 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9379	likely pathogenic
REVEL	0.689	pathogenic-leaning
SaProt	LLR -10.23	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.9, phastCons 1
Overall
CADD	27.7	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 8.48e-05% European (non-Finnish) · 1/1,179,808 alleles

Overall 6.84e-05% 1/1,461,332 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: CLIP4
Protein: p.Pro39Leu
Coding: c.116C>T
MANE Select: NM_018961 · reported on NM_024692
Type: single nucleotide variant
Location: chr2:29121504 (GRCh38)
Structure: AlphaFold pLDDT 82.62 · 2 PDB
Residue 39: the uba domain; an α-helix

Full CLIP4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

UBASH3A p.Ile463Phe Uncertain significance ★★ ⚠ same type
CLIP4 p.Thr555= Benign ★★ same type
UBASH3A c.1393+3A>C Benign ★★ same type
UBASH3A p.Gly601= Benign ★★ same type
UBASH3A p.Ile303= Benign ★★ same type
UBASH3A p.Ile658Val Benign ★★ same type
UBASH3A p.Phe304= Benign ★★ same type
UBASH3A p.Thr144= Benign ★★ 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/clip4-p-pro39leu (accessed [today's date]).

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