Is CAST p.Leu392Phe (c.1174C>T) pathogenic?

CAST p.Leu392Phe (c.1174C>T) is classified Uncertain significance in CAST (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-29). AlphaMissense: likely benign (0.0968); Very rare (popmax 0.00891%, eas).

How common is CAST p.Leu392Phe (c.1174C>T) in the general population?

CAST p.Leu392Phe (c.1174C>T) is very rare (popmax 0.00891%, eas) (gnomAD).

What do computational predictors say about CAST p.Leu392Phe (c.1174C>T)?

AlphaMissense predicts likely benign (score 0.0968) — an in-silico prediction, not a clinical call.

CAST p.Leu392Phe

c.1174C>T · VCV3393722

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0968 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00891%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0968	likely benign
REVEL	0.012	strongly benign-leaning
SaProt	LLR -7.57	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 1.4	GERP -3.1, phastCons 0.69
Overall
CADD	15.54	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 L309F vs ClinVar L392F) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00891% East Asian · 4/44,878 alleles

Filtering AF 0.00298% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0018%

Overall 0.000342% 5/1,461,324 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00891%	11,220
Remaining individualsnot grpmax-eligible	0.0016%	62,472

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.Leu392Phe
Coding: c.1174C>T
Type: single nucleotide variant
Location: chr5:96742730 (GRCh38)
Gene constraint: LOEUF 1.208 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 59.67
Residue 392: the 'disordered' region

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

Similar variants

PCSK1 p.Phe392= Likely benign ★ same residue
CAST p.Leu392fs Likely pathogenic ★ same residue
PCSK1 p.Lys286Ter Pathogenic/Likely pathogenic ★★ same type
CAST p.Ala329Gly Uncertain significance ★★ ⚠ same type
CAST p.Asp160Val Uncertain significance ★★ ⚠ same type
CAST p.Gln731His Uncertain significance ★★ ⚠ same type
CAST p.Glu296Gly Uncertain significance ★★ ⚠ same type
CAST p.Ile274Val 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/cast-p-leu392phe (accessed [today's date]).

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