Is CAST p.Ala348Ser (c.1042G>T) pathogenic?

CAST p.Ala348Ser (c.1042G>T) is classified Uncertain significance in CAST (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-29). AlphaMissense: likely benign (0.1031); Rare (popmax 0.125%, eas); Associated with Inborn genetic diseases.

What condition is associated with CAST p.Ala348Ser (c.1042G>T)?

CAST p.Ala348Ser (c.1042G>T) is associated with Inborn genetic diseases (ClinVar).

How common is CAST p.Ala348Ser (c.1042G>T) in the general population?

CAST p.Ala348Ser (c.1042G>T) is rare (popmax 0.125%, eas) (gnomAD).

What do computational predictors say about CAST p.Ala348Ser (c.1042G>T)?

AlphaMissense predicts likely benign (score 0.1031) — an in-silico prediction, not a clinical call.

CAST p.Ala348Ser

c.1042G>T · rs373460314 · VCV2599097

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1031 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.125%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1031	likely benign
REVEL	0.09	moderately benign-leaning
SaProt	LLR -6.33	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 5.1	GERP 0.88, phastCons 0.98
Overall
CADD	19.2	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 A265S vs ClinVar A348S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.125% East Asian · 56/44,878 alleles

Filtering AF 0.0986% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0892%

Overall 0.00446% 72/1,613,618 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.125%	801
Remaining individualsnot grpmax-eligible	0.016%	6,249
African / African-American	0.004%	25,011
European (non-Finnish)	0.000254%	393,193

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.Ala348Ser
Coding: c.1042G>T
dbSNP: rs373460314
Type: single nucleotide variant
Location: chr5:96741524 (GRCh38)
Gene constraint: LOEUF 1.208 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 59.67
Residue 348: the 'disordered' region

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

Similar variants

PCSK1 p.Ser348= Likely benign ★ same residue
CAST p.Ala329Gly Uncertain significance ★★ ⚠ same condition
CAST p.Asp160Val Uncertain significance ★★ ⚠ same condition
CAST p.Gln731His Uncertain significance ★★ ⚠ same condition
CAST p.Glu296Gly Uncertain significance ★★ ⚠ same condition
CAST p.Ile274Val Uncertain significance ★★ ⚠ same condition
CAST p.Leu586Pro Uncertain significance ★★ ⚠ same condition
CAST p.Ser231Leu Uncertain significance ★★ ⚠ same condition

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-ala348ser (accessed [today's date]).

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