Is CASC3 p.Pro230Thr (c.688C>A) pathogenic?

CASC3 p.Pro230Thr (c.688C>A) is classified Uncertain significance in CASC3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-22). AlphaMissense: likely pathogenic (0.9951); Absent from gnomAD v4.1.

How common is CASC3 p.Pro230Thr (c.688C>A) in the general population?

CASC3 p.Pro230Thr (c.688C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CASC3 p.Pro230Thr (c.688C>A)?

AlphaMissense predicts likely pathogenic (score 0.9951) — an in-silico prediction, not a clinical call.

CASC3 p.Pro230Thr

c.688C>A · rs1989337206 · VCV3137480

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9951 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9951	likely pathogenic · top 4% in CASC3
REVEL	0.837	moderately pathogenic-leaning
SaProt	LLR -13.66	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.4, phastCons 1
Regional constraint	o/e 0.68	unconstrained · MANE · 22 kb · p 5.7e-08 · regional, not allelic
Overall
CADD	28.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CASC3
Protein: p.Pro230Thr
Coding: c.688C>A
MANE Select: NM_007359
dbSNP: rs1989337206
Type: single nucleotide variant
Location: chr17:40162804 (GRCh38)
Gene constraint: LOEUF 0.466 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 54.18 · 13 PDB
Residue 230: the 'disordered' region; the 'necessary for rna-binding, interaction with magoh and localization in nucleus speckles' region; the 'sufficient to form the ejc' region; an α-helix

Full CASC3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CASC3 p.Ala247Val Uncertain significance ★ ⚠ same type
CASC3 p.Ala380Gly Uncertain significance ★ ⚠ same type
CASC3 p.Ala472Val Uncertain significance ★ ⚠ same type
CASC3 p.Ala618Val Uncertain significance ★ ⚠ same type
CASC3 p.Ala641Thr Uncertain significance ★ ⚠ same type
CASC3 p.Ala670Thr Uncertain significance ★ ⚠ same type
CASC3 p.Ala72Ser Uncertain significance ★ ⚠ same type
CASC3 p.Arg207His 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/casc3-p-pro230thr (accessed [today's date]).

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