Is CLIP4 p.Arg686Gln (c.2057G>A) pathogenic?

CLIP4 p.Arg686Gln (c.2057G>A) is classified Uncertain significance in CLIP4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-02). AlphaMissense: likely pathogenic (0.6978); Very rare (popmax 0.00446%, eas).

How common is CLIP4 p.Arg686Gln (c.2057G>A) in the general population?

CLIP4 p.Arg686Gln (c.2057G>A) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about CLIP4 p.Arg686Gln (c.2057G>A)?

AlphaMissense predicts likely pathogenic (score 0.6978) — an in-silico prediction, not a clinical call.

CLIP4 p.Arg686Gln

c.2057G>A · VCV3493739

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6978 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.6978	likely pathogenic
REVEL	0.588	indeterminate
SaProt	LLR -10.16	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.4, phastCons 1
Overall
CADD	26.5	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 0.00446% East Asian · 2/44,892 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.000867% 14/1,614,020 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,446
African / African-American	0.004%	24,974
South Asian	0.0011%	91,064
European (non-Finnish)	0.000678%	147,502

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.Arg686Gln
Coding: c.2057G>A
MANE Select: NM_018961 · reported on NM_024692
Type: single nucleotide variant
Location: chr2:29181832 (GRCh38)
Structure: AlphaFold pLDDT 82.62 · 2 PDB

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-arg686gln (accessed [today's date]).

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