Is CLIP2 p.Arg375Gln (c.1124G>A) pathogenic?

CLIP2 p.Arg375Gln (c.1124G>A) is classified Uncertain significance in CLIP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-16). AlphaMissense: likely pathogenic (0.9193); Very rare (popmax 6.84e-05%).

How common is CLIP2 p.Arg375Gln (c.1124G>A) in the general population?

CLIP2 p.Arg375Gln (c.1124G>A) is very rare (popmax 6.84e-05%) (gnomAD).

What do computational predictors say about CLIP2 p.Arg375Gln (c.1124G>A)?

AlphaMissense predicts likely pathogenic (score 0.9193) — an in-silico prediction, not a clinical call.

CLIP2 p.Arg375Gln

c.1124G>A · VCV4836750

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9193 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.84e-05%)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9193	likely pathogenic
REVEL	0.476	indeterminate
SaProt	LLR -8.28	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 7.4, phastCons 1
Regional constraint	o/e 0.61	unconstrained · MANE · 16 kb · p 2.8e-05 · regional, not allelic
Overall
CADD	29.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 6.84e-05%

Overall 6.84e-05% 1/1,461,686 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: CLIP2
Protein: p.Arg375Gln
Coding: c.1124G>A
MANE Select: NM_003388
Type: single nucleotide variant
Location: chr7:74357386 (GRCh38)
Gene constraint: LOEUF 0.476 · pLI 0.99 (gnomAD)
Structure: AlphaFold pLDDT 75.25 · 2 PDB

Full CLIP2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CLIP2 p.Arg12His Uncertain significance ★★ ⚠ same type
CLIP2 p.Ala123= Benign ★★ same type
CLIP2 p.Arg932= Benign ★★ same type
CLIP2 p.Asn205= Benign ★★ same type
CLIP2 p.Asn910= Benign/Likely benign ★★ same type
CLIP2 p.His159= Benign/Likely benign ★★ same type
CLIP2 p.Ile396= Benign ★★ same type
CLIP2 p.Leu169= 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/clip2-p-arg375gln (accessed [today's date]).

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