Is CASKIN2 p.Arg278Trp (c.832C>T) pathogenic?

CASKIN2 p.Arg278Trp (c.832C>T) is classified Uncertain significance in CASKIN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-03). AlphaMissense: likely pathogenic (0.8661); Ultra-rare (popmax 0.0644%, afr).

How common is CASKIN2 p.Arg278Trp (c.832C>T) in the general population?

CASKIN2 p.Arg278Trp (c.832C>T) is ultra-rare (popmax 0.0644%, afr) (gnomAD).

What do computational predictors say about CASKIN2 p.Arg278Trp (c.832C>T)?

AlphaMissense predicts likely pathogenic (score 0.8661) — an in-silico prediction, not a clinical call.

CASKIN2 p.Arg278Trp

c.832C>T · rs199947018 · VCV3137557

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8661 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0644%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8661	likely pathogenic
REVEL	0.207	benign-leaning
SaProt	LLR -8.08	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.5	GERP 0.45, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 4,779 bp · p 1 · regional, not allelic
Overall
CADD	27.1	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 0.0644% African / African-American · 48/74,582 alleles

Filtering AF 0.0498% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0447%

Overall 0.00403% 65/1,611,902 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0644%	1,554
Remaining individualsnot grpmax-eligible	0.0032%	31,216
East Asian	0.00223%	44,830
South Asian	0.0022%	45,503
Admixed American	0.00167%	59,892
European (non-Finnish)	0.000933%	107,235

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.Arg278Trp
Coding: c.832C>T
MANE Select: NM_020753
dbSNP: rs199947018
Type: single nucleotide variant
Location: chr17:75505824 (GRCh38)
Gene constraint: LOEUF 0.524 · pLI 0.41 (gnomAD)
Structure: AlphaFold pLDDT 58.59 · 4 PDB

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

Similar variants

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
CASKIN2 p.Ala1120Val 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-arg278trp (accessed [today's date]).

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