Is CLIP3 p.Arg433His (c.1298G>A) pathogenic?

CLIP3 p.Arg433His (c.1298G>A) is classified Uncertain significance in CLIP3 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-16). AlphaMissense: ambiguous (0.4476); Rare (popmax 0.495%, mid).

How common is CLIP3 p.Arg433His (c.1298G>A) in the general population?

CLIP3 p.Arg433His (c.1298G>A) is rare (popmax 0.495%, mid) (gnomAD).

What do computational predictors say about CLIP3 p.Arg433His (c.1298G>A)?

AlphaMissense predicts ambiguous (score 0.4476) — an in-silico prediction, not a clinical call.

CLIP3 p.Arg433His

c.1298G>A · rs370765485 · VCV2251204

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4476 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.495%, mid)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4476	ambiguous
REVEL	0.841	moderately pathogenic-leaning
SaProt	LLR -10.59	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.8, phastCons 1
Regional constraint	o/e 0.79	unconstrained · MANE · 2,066 bp · p 0.0017 · regional, not allelic
Overall
CADD	24.7	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 0.495% Middle Eastern · 30/6,062 alleles

Filtering AF 0.356% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.309%

Overall 0.00774% 125/1,614,188 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.495%	202
Remaining individualsnot grpmax-eligible	0.0224%	4,465
African / African-American	0.0187%	5,361
Finnishnot grpmax-eligible	0.00625%	16,009
European (non-Finnish)	0.00483%	20,702
South Asian	0.00439%	22,771
Admixed American	0.00333%	30,012

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: CLIP3
Protein: p.Arg433His
Coding: c.1298G>A
MANE Select: NM_015526
dbSNP: rs370765485
Type: single nucleotide variant
Location: chr19:36017877 (GRCh38)
Gene constraint: LOEUF 0.397 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 74.93 · 1 PDB

Full CLIP3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CLIP3 p.Ala137Val Uncertain significance ★ ⚠ same type
CLIP3 p.Ala148Val Uncertain significance ★ ⚠ same type
CLIP3 p.Ala214Thr Uncertain significance ★ ⚠ same type
CLIP3 p.Ala225Val Uncertain significance ★ ⚠ same type
CLIP3 p.Ala251Val Uncertain significance ★ ⚠ same type
CLIP3 p.Ala271Thr Uncertain significance ★ ⚠ same type
CLIP3 p.Ala30Ser Uncertain significance ★ ⚠ same type
CLIP3 p.Ala7Thr Uncertain significance ★ ⚠ 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/clip3-p-arg433his (accessed [today's date]).

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