Is CLIP1 p.Leu9Phe (c.25C>T) pathogenic?

CLIP1 p.Leu9Phe (c.25C>T) is classified Uncertain significance in CLIP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-05). AlphaMissense: ambiguous (0.4094); Ultra-rare (popmax 0.0267%, eas).

How common is CLIP1 p.Leu9Phe (c.25C>T) in the general population?

CLIP1 p.Leu9Phe (c.25C>T) is ultra-rare (popmax 0.0267%, eas) (gnomAD).

What do computational predictors say about CLIP1 p.Leu9Phe (c.25C>T)?

AlphaMissense predicts ambiguous (score 0.4094) — an in-silico prediction, not a clinical call.

CLIP1 p.Leu9Phe

c.25C>T · VCV3493701

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4094 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0267%, eas)

Computational evidence

Protein change
AlphaMissense	0.4094	ambiguous
REVEL	0.32	indeterminate
SaProt	LLR -11.57	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.5	GERP 1.5, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 2,584 bp · p 0.82 · regional, not allelic
Overall
CADD	23.7	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 0.0267% East Asian · 12/44,866 alleles

Filtering AF 0.0154% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0121%

Overall 0.000806% 13/1,613,090 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0267%	3,739
European (non-Finnish)	8.48e-05%	1,179,536

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: CLIP1
Protein: p.Leu9Phe
Coding: c.25C>T
MANE Select: NM_001247997
Type: single nucleotide variant
Location: chr12:122380428 (GRCh38)
Gene constraint: LOEUF 0.455 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 72.16 · 11 PDB

Full CLIP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CLIP1 p.Ala142Val Uncertain significance ★★ ⚠ same type
CLIP1 p.Arg342Cys Uncertain significance ★★ ⚠ same type
CLIP1 p.Gly1356Arg Uncertain significance ★★ ⚠ same type
CLIP1 p.Lys1267Arg Uncertain significance ★★ ⚠ same type
CLIP1 p.Ala1224Ser Likely benign ★★ same type
CLIP1 p.Ala301= Benign ★★ same type
CLIP1 p.Asn99= Benign/Likely benign ★★ same type
CLIP1 p.Lys851= Likely 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/clip1-p-leu9phe (accessed [today's date]).

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