Is CASS4 p.Arg528Leu (c.1583G>T) pathogenic?

CASS4 p.Arg528Leu (c.1583G>T) is classified Conflicting classifications of pathogenicity in CASS4 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-08-20). AlphaMissense: likely benign (0.1137); Rare (popmax 0.263%, nfe).

How common is CASS4 p.Arg528Leu (c.1583G>T) in the general population?

CASS4 p.Arg528Leu (c.1583G>T) is rare (popmax 0.263%, nfe) (gnomAD).

What do computational predictors say about CASS4 p.Arg528Leu (c.1583G>T)?

AlphaMissense predicts likely benign (score 0.1137) — an in-silico prediction, not a clinical call.

CASS4 p.Arg528Leu

c.1583G>T · rs148921681 · VCV778178

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1137 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.263%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1137	likely benign
REVEL	0.093	moderately benign-leaning
SaProt	LLR -8.09	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 0.75	GERP -4.3, phastCons 0.011
Regional constraint	o/e 0.87	unconstrained · MANE · 46 kb · p 2.4e-05 · regional, not allelic
Overall
CADD	13.97	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 0.263% European (non-Finnish) · 3,102/1,180,006 alleles

Filtering AF 0.255% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.252%

Overall 0.215% 3,469/1,613,954 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.263%	380
Finnishnot grpmax-eligible	0.241%	416
Remaining individualsnot grpmax-eligible	0.213%	470
Admixed American	0.075%	1,333
Middle Eastern	0.033%	3,031
African / African-American	0.032%	3,123
Ashkenazi Jewishnot grpmax-eligible	0.0135%	7,401
South Asian	0.00549%	18,213

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: CASS4
Protein: p.Arg528Leu
Coding: c.1583G>T
MANE Select: NM_020356
dbSNP: rs148921681
Type: single nucleotide variant
Location: chr20:56452759 (GRCh38)
Gene constraint: LOEUF 0.53 · pLI 0.88 (gnomAD)
Structure: AlphaFold pLDDT 58.88 · 1 PDB

Full CASS4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CASS4 p.Arg528Cys Uncertain significance ★ ⚠ same residue
CASS4 p.Arg528Gly Uncertain significance ★ ⚠ same residue
CASS4 p.Arg528His Uncertain significance ★ ⚠ same residue
CASS4 p.Arg491Lys Benign ★★ same type
CASS4 p.Leu71= Benign ★★ same type
CASS4 p.Ser426Leu Benign ★★ ⚠ same type
CASS4 p.Ala10Val Uncertain significance ★ ⚠ same type
CASS4 p.Ala16Asp 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/cass4-p-arg528leu (accessed [today's date]).

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