Is CASKIN2 p.Glu178Asp (c.534G>C) pathogenic?

CASKIN2 p.Glu178Asp (c.534G>C) is classified Uncertain significance in CASKIN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-20). AlphaMissense: likely pathogenic (0.71); Ultra-rare (popmax 0.0232%, nfe).

How common is CASKIN2 p.Glu178Asp (c.534G>C) in the general population?

CASKIN2 p.Glu178Asp (c.534G>C) is ultra-rare (popmax 0.0232%, nfe) (gnomAD).

What do computational predictors say about CASKIN2 p.Glu178Asp (c.534G>C)?

AlphaMissense predicts likely pathogenic (score 0.71) — an in-silico prediction, not a clinical call.

CASKIN2 p.Glu178Asp

c.534G>C · rs143653140 · VCV2382999

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.71 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0232%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.71	likely pathogenic
REVEL	0.233	benign-leaning
SaProt	LLR -6.09	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>T here scores Δ0.20 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.74	GERP -0.92, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 65 bp · p 0.66 · regional, not allelic
Overall
CADD	22.0	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 0.0232% European (non-Finnish) · 274/1,179,982 alleles

Filtering AF 0.021% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0201%

Overall 0.0176% 284/1,613,302 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0232%	4,307
Remaining individualsnot grpmax-eligible	0.0096%	10,411
African / African-American	0.00401%	24,947
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,604

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.Glu178Asp
Coding: c.534G>C
MANE Select: NM_020753
dbSNP: rs143653140
Type: single nucleotide variant
Location: chr17:75506666 (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-glu178asp (accessed [today's date]).

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