Is CASKIN1 p.Val993Met (c.2977G>A) pathogenic?

CASKIN1 p.Val993Met (c.2977G>A) is classified Uncertain significance in CASKIN1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-26). AlphaMissense: likely benign (0.2567); Very rare (popmax 0.000939%, nfe).

How common is CASKIN1 p.Val993Met (c.2977G>A) in the general population?

CASKIN1 p.Val993Met (c.2977G>A) is very rare (popmax 0.000939%, nfe) (gnomAD).

What do computational predictors say about CASKIN1 p.Val993Met (c.2977G>A)?

AlphaMissense predicts likely benign (score 0.2567) — an in-silico prediction, not a clinical call.

CASKIN1 p.Val993Met

c.2977G>A · VCV4648392

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2567 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000939%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2567	likely benign
REVEL	0.151	moderately benign-leaning
SaProt	LLR -7.94	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 7.6	GERP 1.7, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 8,517 bp · p 0.0017 · regional, not allelic
Overall
CADD	25.4	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 0.000939% European (non-Finnish) · 11/1,171,648 alleles

Filtering AF 0.000504% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000368%

Overall 0.000695% 11/1,582,848 alleles · very rare exomes 10/1,430,630 · genomes 1/152,218 · joint denominator

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: CASKIN1
Protein: p.Val993Met
Coding: c.2977G>A
MANE Select: NM_020764
Type: single nucleotide variant
Location: chr16:2180391 (GRCh38)
Gene constraint: LOEUF 0.614 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 54.22 · 3 PDB

Full CASKIN1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CASKIN1 p.Ala89Val Uncertain significance ★★ ⚠ same type
CASKIN1 p.Arg699Gln Uncertain significance ★★ ⚠ same type
CASKIN1 p.Ala1005Thr Uncertain significance ★ ⚠ same type
CASKIN1 p.Ala1005Val Uncertain significance ★ ⚠ same type
CASKIN1 p.Ala1019Ser Uncertain significance ★ ⚠ same type
CASKIN1 p.Ala1019Thr Uncertain significance ★ ⚠ same type
CASKIN1 p.Ala1045Thr Uncertain significance ★ ⚠ same type
CASKIN1 p.Ala1108Gly 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/caskin1-p-val993met (accessed [today's date]).

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