Is CASKIN2 p.Arg618Trp (c.1852C>T) pathogenic?

CASKIN2 p.Arg618Trp (c.1852C>T) is classified Uncertain significance in CASKIN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-07). AlphaMissense: ambiguous (0.4825); Ultra-rare (popmax 0.0136%, amr).

How common is CASKIN2 p.Arg618Trp (c.1852C>T) in the general population?

CASKIN2 p.Arg618Trp (c.1852C>T) is ultra-rare (popmax 0.0136%, amr) (gnomAD).

What do computational predictors say about CASKIN2 p.Arg618Trp (c.1852C>T)?

AlphaMissense predicts ambiguous (score 0.4825) — an in-silico prediction, not a clinical call.

CASKIN2 p.Arg618Trp

c.1852C>T · VCV3485149

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4825 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0136%, amr)

Computational evidence

Protein change
AlphaMissense	0.4825	ambiguous
REVEL	0.343	indeterminate
SaProt	LLR -13.58	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.1	GERP 0.4, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 4,779 bp · p 1 · regional, not allelic
Overall
CADD	24.1	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 0.0136% Admixed American · 8/58,792 alleles

Filtering AF 0.00673% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00491%

Overall 0.00338% 54/1,596,882 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.104%	962
Admixed Americangrpmax	0.0136%	7,349
South Asian	0.00445%	22,451
Remaining individualsnot grpmax-eligible	0.00324%	30,896
East Asian	0.00224%	44,670
African / African-American	0.00134%	74,740
European (non-Finnish)	0.000682%	146,658

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: CASKIN2
Protein: p.Arg618Trp
Coding: c.1852C>T
MANE Select: NM_020753
Type: single nucleotide variant
Location: chr17:75503222 (GRCh38)
Gene constraint: LOEUF 0.524 · pLI 0.41 (gnomAD)
Structure: AlphaFold pLDDT 58.59 · 4 PDB
Residue 618: an α-helix; the sam 2 domain

Full CASKIN2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CASKIN2 p.Arg618Gln Uncertain significance ★ ⚠ same residue
CASKIN2 c.1467+8C>A Benign ★★ same type
CASKIN2 p.Ala1005Glu Uncertain significance ★ ⚠ same type
CASKIN2 p.Ala1005Thr Uncertain significance ★ ⚠ same type
CASKIN2 p.Ala1087Gly Uncertain significance ★ ⚠ same type
CASKIN2 p.Ala1087Val Uncertain significance ★ ⚠ same type
CASKIN2 p.Ala1088Thr Uncertain significance ★ ⚠ same type
CASKIN2 p.Ala111Thr 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/caskin2-p-arg618trp (accessed [today's date]).

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