Is CLIP4 p.Arg577Lys (c.1730G>A) pathogenic?

CLIP4 p.Arg577Lys (c.1730G>A) is classified Uncertain significance in CLIP4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-20). AlphaMissense: likely benign (0.1611); Very rare (popmax 0.00224%, eas).

How common is CLIP4 p.Arg577Lys (c.1730G>A) in the general population?

CLIP4 p.Arg577Lys (c.1730G>A) is very rare (popmax 0.00224%, eas) (gnomAD).

What do computational predictors say about CLIP4 p.Arg577Lys (c.1730G>A)?

AlphaMissense predicts likely benign (score 0.1611) — an in-silico prediction, not a clinical call.

CLIP4 p.Arg577Lys

c.1730G>A · VCV4003710

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1611 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00224%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1611	likely benign
REVEL	0.165	moderately benign-leaning
SaProt	LLR -6.47	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.23 · evaluated, not missing
Constraint at this position
Conservation	phyloP 12	GERP 2.9, phastCons 1
Overall
CADD	23.6	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 0.00224% East Asian · 1/44,696 alleles

Overall 6.86e-05% 1/1,458,076 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.Arg577Lys
Coding: c.1730G>A
MANE Select: NM_018961 · reported on NM_024692
Type: single nucleotide variant
Location: chr2:29174379 (GRCh38)
Structure: AlphaFold pLDDT 82.62 · 2 PDB
Residue 577: the 'phosphatase-like' region

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

Similar variants

UBASH3A p.Pro577Leu Uncertain significance ★ ⚠ same residue
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

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-arg577lys (accessed [today's date]).

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