Is CASKIN2 p.Pro727Arg (c.2180C>G) pathogenic?

CASKIN2 p.Pro727Arg (c.2180C>G) is classified Uncertain significance in CASKIN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-04). AlphaMissense: likely benign (0.0905); Rare (popmax 0.681%, afr).

How common is CASKIN2 p.Pro727Arg (c.2180C>G) in the general population?

CASKIN2 p.Pro727Arg (c.2180C>G) is rare (popmax 0.681%, afr) (gnomAD).

What do computational predictors say about CASKIN2 p.Pro727Arg (c.2180C>G)?

AlphaMissense predicts likely benign (score 0.0905) — an in-silico prediction, not a clinical call.

CASKIN2 p.Pro727Arg

c.2180C>G · VCV4219323

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0905 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.681%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0905	likely benign
REVEL	0.074	moderately benign-leaning
SaProt	LLR -6.84	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 1	GERP -3.1, phastCons 0.36
Regional constraint	o/e 1.00	unconstrained · MANE · 4,779 bp · p 1 · regional, not allelic
Overall
CADD	7.684	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 0.681% African / African-American · 498/73,148 alleles

Filtering AF 0.631% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.612%

Overall 0.0447% 690/1,544,942 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.681%	147
Middle Eastern	0.123%	816
Remaining individualsnot grpmax-eligible	0.042%	2,380
Admixed American	0.0289%	3,465
European (non-Finnish)	0.0118%	8,483
South Asian	0.00875%	11,431
East Asian	0.00677%	14,761

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.Pro727Arg
Coding: c.2180C>G
MANE Select: NM_020753
Type: single nucleotide variant
Location: chr17:75502894 (GRCh38)
Gene constraint: LOEUF 0.524 · pLI 0.41 (gnomAD)
Structure: AlphaFold pLDDT 58.59 · 4 PDB
Residue 727: the 'disordered' region

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

Similar variants

CASKIN2 p.Pro727Ala Uncertain significance ★ ⚠ same residue
CASKIN2 p.Pro727His 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

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-pro727arg (accessed [today's date]).

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