Is CASC3 p.Ser75Trp (c.224C>G) pathogenic?

CASC3 p.Ser75Trp (c.224C>G) is classified Uncertain significance in CASC3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-07). AlphaMissense: likely pathogenic (0.912); Very rare (popmax 0.00233%, afr).

How common is CASC3 p.Ser75Trp (c.224C>G) in the general population?

CASC3 p.Ser75Trp (c.224C>G) is very rare (popmax 0.00233%, afr) (gnomAD).

What do computational predictors say about CASC3 p.Ser75Trp (c.224C>G)?

AlphaMissense predicts likely pathogenic (score 0.912) — an in-silico prediction, not a clinical call.

CASC3 p.Ser75Trp

c.224C>G · VCV4648362

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.912 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00233%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.912	likely pathogenic
REVEL	0.163	moderately benign-leaning
SaProt	LLR -10.60	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.36 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.4	GERP 1.6, phastCons 1
Regional constraint	o/e 1.30	unconstrained · MANE · 675 bp · p 0.00086 · regional, not allelic
Overall
CADD	32.0	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 0.00233% African / African-American · 1/43,010 alleles

Filtering AF 0.000163% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000118%

Overall 0.000584% 6/1,027,596 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00233%	43,010
European (non-Finnish)	0.000556%	179,914

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: CASC3
Protein: p.Ser75Trp
Coding: c.224C>G
MANE Select: NM_007359
Type: single nucleotide variant
Location: chr17:40140772 (GRCh38)
Gene constraint: LOEUF 0.466 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 54.18 · 13 PDB
Residue 75: the 'disordered' region

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

Similar variants

CASC3 p.Ser75Leu Uncertain significance ★ ⚠ same residue
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

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-ser75trp (accessed [today's date]).

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