Is CASC3 p.Arg299Ser (c.897G>C) pathogenic?

CASC3 p.Arg299Ser (c.897G>C) is classified Uncertain significance in CASC3 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-17). AlphaMissense: likely pathogenic (0.7475); Ultra-rare (popmax 0.0143%, sas).

How common is CASC3 p.Arg299Ser (c.897G>C) in the general population?

CASC3 p.Arg299Ser (c.897G>C) is ultra-rare (popmax 0.0143%, sas) (gnomAD).

What do computational predictors say about CASC3 p.Arg299Ser (c.897G>C)?

AlphaMissense predicts likely pathogenic (score 0.7475) — an in-silico prediction, not a clinical call.

CASC3 p.Arg299Ser

c.897G>C · rs201628547 · VCV2382949

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7475 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0143%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.7475	likely pathogenic
REVEL	0.298	indeterminate
SaProt	LLR -7.34	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.7	GERP -0.92, phastCons 1
Regional constraint	o/e 0.68	unconstrained · MANE · 22 kb · p 5.7e-08 · regional, not allelic
Overall
CADD	23.0	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 0.0143% South Asian · 13/91,088 alleles

Filtering AF 0.00844% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00661%

Overall 0.00638% 103/1,614,006 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0143%	7,007
European (non-Finnish)	0.00686%	14,568
Remaining individualsnot grpmax-eligible	0.0064%	15,622
African / African-American	0.00534%	18,720
Admixed American	0.00167%	59,984

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.Arg299Ser
Coding: c.897G>C
MANE Select: NM_007359
dbSNP: rs201628547
Type: single nucleotide variant
Location: chr17:40163592 (GRCh38)
Gene constraint: LOEUF 0.466 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 54.18 · 13 PDB
Residue 299: the 'disordered' 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-arg299ser (accessed [today's date]).

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