Is CASKIN2 p.Val247Ala (c.740T>C) pathogenic?

CASKIN2 p.Val247Ala (c.740T>C) is classified Uncertain significance in CASKIN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-20). AlphaMissense: ambiguous (0.5031); Very rare (popmax 0.0078%, nfe).

How common is CASKIN2 p.Val247Ala (c.740T>C) in the general population?

CASKIN2 p.Val247Ala (c.740T>C) is very rare (popmax 0.0078%, nfe) (gnomAD).

What do computational predictors say about CASKIN2 p.Val247Ala (c.740T>C)?

AlphaMissense predicts ambiguous (score 0.5031) — an in-silico prediction, not a clinical call.

CASKIN2 p.Val247Ala

c.740T>C · rs145076892 · VCV3137554

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5031 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0078%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.5031	ambiguous
REVEL	0.205	benign-leaning
SaProt	LLR -8.88	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7	GERP 0.47, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 539 bp · p 0.034 · regional, not allelic
Overall
CADD	24.7	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 0.0078% European (non-Finnish) · 92/1,179,932 alleles

Filtering AF 0.00648% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.006%

Overall 0.00601% 97/1,613,386 alleles · very rare exomes 95/1,461,262 · genomes 2/152,124 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0078%	12,825
Remaining individualsnot grpmax-eligible	0.0032%	31,235
Finnishnot grpmax-eligible	0.00315%	31,780
Admixed American	0.00167%	59,978

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.Val247Ala
Coding: c.740T>C
MANE Select: NM_020753
dbSNP: rs145076892
Type: single nucleotide variant
Location: chr17:75505916 (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 p.Val247Met 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-val247ala (accessed [today's date]).

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