Is CLIP2 p.Val780Ile (c.2338G>A) pathogenic?

CLIP2 p.Val780Ile (c.2338G>A) is classified Uncertain significance in CLIP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-23). AlphaMissense: likely benign (0.0886); Ultra-rare (popmax 0.0117%, amr).

How common is CLIP2 p.Val780Ile (c.2338G>A) in the general population?

CLIP2 p.Val780Ile (c.2338G>A) is ultra-rare (popmax 0.0117%, amr) (gnomAD).

What do computational predictors say about CLIP2 p.Val780Ile (c.2338G>A)?

AlphaMissense predicts likely benign (score 0.0886) — an in-silico prediction, not a clinical call.

CLIP2 p.Val780Ile

c.2338G>A · VCV3267758

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0886 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0117%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0886	likely benign
REVEL	0.132	moderately benign-leaning
SaProt	LLR -6.76	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 8.4	GERP 6.4, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 31 kb · p 0.00026 · regional, not allelic
Overall
CADD	16.96	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 0.0117% Admixed American · 7/59,830 alleles

Filtering AF 0.00545% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00381%

Overall 0.0013% 21/1,612,914 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0117%	8,547
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,556
Remaining individualsnot grpmax-eligible	0.0032%	31,232
African / African-American	0.00133%	75,050
European (non-Finnish)	0.000848%	117,975

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.Val780Ile
Coding: c.2338G>A
MANE Select: NM_003388
Type: single nucleotide variant
Location: chr7:74376739 (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-val780ile (accessed [today's date]).

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