Is CASS4 p.Arg491Lys (c.1472G>A) pathogenic?

CASS4 p.Arg491Lys (c.1472G>A) is classified Benign in CASS4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2018-01-19). AlphaMissense: likely benign (0.0844); Low-frequency (popmax 3.37%, afr).

How common is CASS4 p.Arg491Lys (c.1472G>A) in the general population?

CASS4 p.Arg491Lys (c.1472G>A) is low-frequency (popmax 3.37%, afr) (gnomAD).

What do computational predictors say about CASS4 p.Arg491Lys (c.1472G>A)?

AlphaMissense predicts likely benign (score 0.0844) — an in-silico prediction, not a clinical call.

CASS4 p.Arg491Lys

c.1472G>A · rs16979936 · VCV788688

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0844 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 3.37%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0844	likely benign
REVEL	0.067	moderately benign-leaning
SaProt	LLR -6.22	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 6.7	GERP -0.35, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 46 kb · p 2.4e-05 · regional, not allelic
Overall
CADD	17.45	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 3.37% African / African-American · 2,528/75,030 alleles

Filtering AF 3.26% ClinGen BA1/BS1 input FAF95, joint · FAF99 3.22%

Overall 0.178% 2,868/1,614,170 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	3.37%	30
Remaining individualsnot grpmax-eligible	0.245%	409
Admixed American	0.223%	448
Middle Eastern	0.165%	606
South Asian	0.0121%	8,280
European (non-Finnish)	0.00271%	36,876

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.Arg491Lys
Coding: c.1472G>A
MANE Select: NM_020356
dbSNP: rs16979936
Type: single nucleotide variant
Location: chr20:56452648 (GRCh38)
Gene constraint: LOEUF 0.53 · pLI 0.88 (gnomAD)
Structure: AlphaFold pLDDT 58.88 · 1 PDB
Residue 491: a UniProt-annotated variant site (in)

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

Similar variants

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
CASS4 p.Ala271Thr Uncertain significance ★ ⚠ same type
CASS4 p.Ala377Val Uncertain significance ★ ⚠ same type
CASS4 p.Ala456Thr Uncertain significance ★ ⚠ same type
CASS4 p.Ala682Val 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-arg491lys (accessed [today's date]).

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