Is CASS4 p.Val255Ile (c.763G>A) pathogenic?

CASS4 p.Val255Ile (c.763G>A) is classified Likely benign in CASS4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-28). AlphaMissense: likely benign (0.0714); Ultra-rare (popmax 0.0133%, amr).

How common is CASS4 p.Val255Ile (c.763G>A) in the general population?

CASS4 p.Val255Ile (c.763G>A) is ultra-rare (popmax 0.0133%, amr) (gnomAD).

What do computational predictors say about CASS4 p.Val255Ile (c.763G>A)?

AlphaMissense predicts likely benign (score 0.0714) — an in-silico prediction, not a clinical call.

CASS4 p.Val255Ile

c.763G>A · rs73159591 · VCV3137688

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0714 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0133%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0714	likely benign
REVEL	0.006	strongly benign-leaning
SaProt	LLR -6.89	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 -2.1	GERP -4.7
Regional constraint	o/e 0.87	unconstrained · MANE · 46 kb · p 2.4e-05 · regional, not allelic
Overall
CADD	0.011	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 0.0133% Admixed American · 8/60,018 alleles

Filtering AF 0.00661% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00482%

Overall 0.0026% 42/1,614,186 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0133%	7,502
European (non-Finnish)	0.00263%	38,066
East Asian	0.00223%	44,884
Remaining individualsnot grpmax-eligible	0.0016%	62,508
South Asian	0.0011%	91,080

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.Val255Ile
Coding: c.763G>A
MANE Select: NM_020356
dbSNP: rs73159591
Type: single nucleotide variant
Location: chr20:56451939 (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.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
CASS4 p.Ala271Thr Uncertain significance ★ ⚠ same type
CASS4 p.Ala377Val Uncertain significance ★ ⚠ same type
CASS4 p.Ala456Thr 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-val255ile (accessed [today's date]).

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