Is CLIP3 p.Arg178His (c.533G>A) pathogenic?

CLIP3 p.Arg178His (c.533G>A) is classified Uncertain significance in CLIP3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-01-17). AlphaMissense: likely benign (0.2128); Ultra-rare (popmax 0.0164%, mid).

How common is CLIP3 p.Arg178His (c.533G>A) in the general population?

CLIP3 p.Arg178His (c.533G>A) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about CLIP3 p.Arg178His (c.533G>A)?

AlphaMissense predicts likely benign (score 0.2128) — an in-silico prediction, not a clinical call.

CLIP3 p.Arg178His

c.533G>A · rs752645258 · VCV2470797

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2128 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2128	likely benign
REVEL	0.366	indeterminate
SaProt	LLR -2.16	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.8, phastCons 1
Regional constraint	o/e 0.59	unconstrained · MANE · 7,759 bp · p 1.5e-13 · regional, not allelic
Overall
CADD	28.7	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 0.0164% Middle Eastern · 1/6,082 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000558% 9/1,613,606 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,082
Admixed American	0.00167%	59,996
African / African-American	0.00133%	74,944
European (non-Finnish)	0.000509%	196,656

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.Arg178His
Coding: c.533G>A
MANE Select: NM_015526
dbSNP: rs752645258
Type: single nucleotide variant
Location: chr19:36026615 (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-arg178his (accessed [today's date]).

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