Is CASKIN2 p.Leu295Phe (c.883C>T) pathogenic?

CASKIN2 p.Leu295Phe (c.883C>T) is classified Uncertain significance in CASKIN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-15). AlphaMissense: ambiguous (0.3641); Rare (popmax 0.249%, afr).

How common is CASKIN2 p.Leu295Phe (c.883C>T) in the general population?

CASKIN2 p.Leu295Phe (c.883C>T) is rare (popmax 0.249%, afr) (gnomAD).

What do computational predictors say about CASKIN2 p.Leu295Phe (c.883C>T)?

AlphaMissense predicts ambiguous (score 0.3641) — an in-silico prediction, not a clinical call.

CASKIN2 p.Leu295Phe

c.883C>T · VCV3827525

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3641 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.249%, afr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3641	ambiguous
REVEL	0.216	benign-leaning
SaProt	LLR -7.43	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.5	GERP 1.7, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 4,779 bp · p 1 · regional, not allelic
Overall
CADD	26.0	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 0.249% African / African-American · 187/75,000 alleles

Filtering AF 0.22% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.209%

Overall 0.0129% 208/1,613,566 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.249%	401
Admixed American	0.0233%	4,287
Remaining individualsnot grpmax-eligible	0.0064%	15,624
European (non-Finnish)	0.000254%	393,335

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.Leu295Phe
Coding: c.883C>T
MANE Select: NM_020753
Type: single nucleotide variant
Location: chr17:75505604 (GRCh38)
Gene constraint: LOEUF 0.524 · pLI 0.41 (gnomAD)
Structure: AlphaFold pLDDT 58.59 · 4 PDB
Residue 295: the sh3 domain

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

Similar variants

CASKIN2 p.Leu295Val 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-leu295phe (accessed [today's date]).

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