Is CASC3 p.Arg409Lys (c.1226G>A) pathogenic?

CASC3 p.Arg409Lys (c.1226G>A) is classified Uncertain significance in CASC3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-16). AlphaMissense: ambiguous (0.4419); Absent from gnomAD v4.1.

How common is CASC3 p.Arg409Lys (c.1226G>A) in the general population?

CASC3 p.Arg409Lys (c.1226G>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CASC3 p.Arg409Lys (c.1226G>A)?

AlphaMissense predicts ambiguous (score 0.4419) — an in-silico prediction, not a clinical call.

CASC3 p.Arg409Lys

c.1226G>A · rs2544339805 · VCV3137471

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4419 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4419	ambiguous
REVEL	0.203	benign-leaning
SaProt	LLR -6.96	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 9.9	GERP 1.4, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 5,984 bp · p 0.062 · regional, not allelic
Overall
CADD	26.9	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

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.Arg409Lys
Coding: c.1226G>A
MANE Select: NM_007359
dbSNP: rs2544339805
Type: single nucleotide variant
Location: chr17:40163921 (GRCh38)
Gene constraint: LOEUF 0.466 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 54.18 · 13 PDB
Residue 409: the 'disordered' region; the 'necessary for localization in cytoplasmic stress granules' region

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-arg409lys (accessed [today's date]).

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