Is CLIP1 p.Phe486Leu (c.1458T>G) pathogenic?

CLIP1 p.Phe486Leu (c.1458T>G) is classified Uncertain significance in CLIP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-24). AlphaMissense: likely pathogenic (0.9939); Very rare (popmax 0.00267%, afr).

How common is CLIP1 p.Phe486Leu (c.1458T>G) in the general population?

CLIP1 p.Phe486Leu (c.1458T>G) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about CLIP1 p.Phe486Leu (c.1458T>G)?

AlphaMissense predicts likely pathogenic (score 0.9939) — an in-silico prediction, not a clinical call.

CLIP1 p.Phe486Leu

c.1458T>G · rs899229922 · VCV2529126

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9939 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9939	likely pathogenic · top 5% in CLIP1
REVEL	0.287	benign-leaning
SaProt	LLR -3.95	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	Δ0.20	donor gain · deltas
Constraint at this position
Conservation	phyloP 11	GERP 1.8, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 78 kb · p 3e-08 · regional, not allelic
Overall
CADD	25.2	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 0.00267% African / African-American · 2/74,936 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.00131% 2/152,234 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: CLIP1
Protein: p.Phe486Leu
Coding: c.1458T>G
MANE Select: NM_001247997
dbSNP: rs899229922
Type: single nucleotide variant
Location: chr12:122347423 (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-phe486leu (accessed [today's date]).

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