Is CASS4 p.Leu460Pro (c.1379T>C) pathogenic?

CASS4 p.Leu460Pro (c.1379T>C) is classified Uncertain significance in CASS4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-11). AlphaMissense: ambiguous (0.4364); Very rare (popmax 0.00133%, afr).

How common is CASS4 p.Leu460Pro (c.1379T>C) in the general population?

CASS4 p.Leu460Pro (c.1379T>C) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about CASS4 p.Leu460Pro (c.1379T>C)?

AlphaMissense predicts ambiguous (score 0.4364) — an in-silico prediction, not a clinical call.

CASS4 p.Leu460Pro

c.1379T>C · VCV3827629

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4364 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4364	ambiguous
REVEL	0.191	benign-leaning
SaProt	LLR -5.34	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.3	GERP 0.37, phastCons 0.75
Regional constraint	o/e 0.87	unconstrained · MANE · 46 kb · p 2.4e-05 · regional, not allelic
Overall
CADD	22.4	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 0.00133% African / African-American · 1/75,044 alleles

Overall 6.84e-05% 1/1,461,874 alleles · very rare

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.Leu460Pro
Coding: c.1379T>C
MANE Select: NM_020356
Type: single nucleotide variant
Location: chr20:56452555 (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-leu460pro (accessed [today's date]).

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