Is CAST p.Leu618Phe (c.1852C>T) pathogenic?

CAST p.Leu618Phe (c.1852C>T) is classified Uncertain significance in CAST (ClinVar, Single submitter, 1 submitter; last evaluated 2022-01-04). AlphaMissense: likely benign (0.146); Very rare (popmax 0.00346%, amr); Associated with Inborn genetic diseases.

What condition is associated with CAST p.Leu618Phe (c.1852C>T)?

CAST p.Leu618Phe (c.1852C>T) is associated with Inborn genetic diseases (ClinVar).

How common is CAST p.Leu618Phe (c.1852C>T) in the general population?

CAST p.Leu618Phe (c.1852C>T) is very rare (popmax 0.00346%, amr) (gnomAD).

What do computational predictors say about CAST p.Leu618Phe (c.1852C>T)?

AlphaMissense predicts likely benign (score 0.146) — an in-silico prediction, not a clinical call.

CAST p.Leu618Phe

c.1852C>T · rs375069165 · VCV2269889

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.146 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00346%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.146	likely benign
REVEL	0.231	benign-leaning
SaProt	LLR -7.78	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 1.8	GERP 2.1, phastCons 1
Overall
CADD	24.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM L535F vs ClinVar L618F) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00346% Admixed American · 2/57,846 alleles

Filtering AF 0.000573% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000215%

Overall 0.000413% 6/1,454,406 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00346%	28,923
European (non-Finnish)	0.00034%	294,412

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: CAST
Protein: p.Leu618Phe
Coding: c.1852C>T
MANE Select: NM_001040458 · reported on NM_001750
dbSNP: rs375069165
Type: single nucleotide variant
Location: chr5:96762292 (GRCh38)

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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/cast-p-leu618phe (accessed [today's date]).

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