Is CAST p.Ser378Leu (c.1133C>T) pathogenic?

CAST p.Ser378Leu (c.1133C>T) is classified Conflicting classifications of pathogenicity in CAST (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-09-03). AlphaMissense: likely benign (0.1446); Ultra-rare (popmax 0.0591%, nfe).

How common is CAST p.Ser378Leu (c.1133C>T) in the general population?

CAST p.Ser378Leu (c.1133C>T) is ultra-rare (popmax 0.0591%, nfe) (gnomAD).

What do computational predictors say about CAST p.Ser378Leu (c.1133C>T)?

AlphaMissense predicts likely benign (score 0.1446) — an in-silico prediction, not a clinical call.

CAST p.Ser378Leu

c.1133C>T · rs149270486 · VCV1556034

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1446 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0591%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1446	likely benign
REVEL	0.215	benign-leaning
SaProt	LLR -9.68	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.26 · evaluated, not missing
Constraint at this position
Conservation	phyloP 4.8	GERP 2.7, phastCons 1
Overall
CADD	26.0	PHRED · no single calibrated threshold — expert panels disagree

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM S295L vs ClinVar S378L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0591% European (non-Finnish) · 697/1,179,836 alleles

Filtering AF 0.0554% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.054%

Overall 0.0572% 923/1,613,790 alleles · ultra-rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.298%	335
European (non-Finnish)grpmax	0.0591%	1,693
Remaining individualsnot grpmax-eligible	0.0352%	2,840
Admixed American	0.0133%	7,499
African / African-American	0.00667%	14,982

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ser378Leu
Coding: c.1133C>T
dbSNP: rs149270486
Type: single nucleotide variant
Location: chr5:96742689 (GRCh38)
Gene constraint: LOEUF 1.208 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 59.67
Residue 378: the 'disordered' region

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

Similar variants

CAST p.Ser378= Likely benign ★ 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
CAST p.Leu586Pro 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-ser378leu (accessed [today's date]).

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