Is CLIP1 p.Ile461Val (c.1381A>G) pathogenic?

CLIP1 p.Ile461Val (c.1381A>G) is classified Uncertain significance in CLIP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-03). AlphaMissense: likely benign (0.2318); Ultra-rare (popmax 0.0167%, afr); Associated with CLIP1-related intellectual disability.

What condition is associated with CLIP1 p.Ile461Val (c.1381A>G)?

CLIP1 p.Ile461Val (c.1381A>G) is associated with CLIP1-related intellectual disability (ClinVar).

How common is CLIP1 p.Ile461Val (c.1381A>G) in the general population?

CLIP1 p.Ile461Val (c.1381A>G) is ultra-rare (popmax 0.0167%, afr) (gnomAD).

What do computational predictors say about CLIP1 p.Ile461Val (c.1381A>G)?

AlphaMissense predicts likely benign (score 0.2318) — an in-silico prediction, not a clinical call.

CLIP1 p.Ile461Val

c.1381A>G · rs746134099 · VCV1696623

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2318 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0167%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

CLIP1-related intellectual disability

Computational evidence

Protein change
AlphaMissense	0.2318	likely benign
REVEL	0.129	moderately benign-leaning
SaProt	LLR -5.57	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.2	GERP 1.9, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 78 kb · p 3e-08 · regional, not allelic
Overall
CADD	22.1	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 0.0167% African / African-American · 12/71,948 alleles

Filtering AF 0.00956% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00749%

Overall 0.0027% 41/1,516,578 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0167%	5,996
Remaining individualsnot grpmax-eligible	0.00509%	19,645
European (non-Finnish)	0.00228%	43,895

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.Ile461Val
Coding: c.1381A>G
MANE Select: NM_001247997
dbSNP: rs746134099
Type: single nucleotide variant
Location: chr12:122351131 (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

Disease context

CLIP1-related intellectual disability

Similar variants

CLIP1 p.Lys1267Arg Uncertain significance ★★ ⚠ same condition
CLIP1 p.Lys1373Arg Uncertain significance ★ ⚠ same condition
CLIP1 p.Ala1174= Likely benign same condition
CLIP1 p.Asn1263= Likely benign same condition
CLIP1 p.Gln1120His Likely benign ⚠ same condition
CLIP1 p.Ile631= Likely benign same condition
CLIP1 p.Thr27Met Benign ⚠ same condition
CLIP1 p.Thr339= Likely benign same condition

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-ile461val (accessed [today's date]).

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