Is CAST p.Ala775Val (c.2324C>T) pathogenic?

CAST p.Ala775Val (c.2324C>T) is classified Uncertain significance in CAST (ClinVar, Single submitter, 2 submitters; last evaluated 2026-05-05). AlphaMissense: likely benign (0.1175); Very rare (popmax 0.00334%, amr); Associated with Inborn genetic diseases.

What condition is associated with CAST p.Ala775Val (c.2324C>T)?

CAST p.Ala775Val (c.2324C>T) is associated with Inborn genetic diseases (ClinVar).

How common is CAST p.Ala775Val (c.2324C>T) in the general population?

CAST p.Ala775Val (c.2324C>T) is very rare (popmax 0.00334%, amr) (gnomAD).

What do computational predictors say about CAST p.Ala775Val (c.2324C>T)?

AlphaMissense predicts likely benign (score 0.1175) — an in-silico prediction, not a clinical call.

CAST p.Ala775Val

c.2324C>T · rs767408102 · VCV3137697

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1175 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00334%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1175	likely benign
REVEL	0.055	moderately benign-leaning
SaProt	LLR -7.42	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.25	donor gain · deltas
Pangolin	Δ0.20	gain · loss 0.07 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 1.6	GERP 2.1, phastCons 0.89
Overall
CADD	23.9	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 A692V vs ClinVar A775V) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00334% Admixed American · 2/59,952 alleles

Filtering AF 0.0024% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0021%

Overall 0.00254% 41/1,611,262 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00334%	29,976
European (non-Finnish)	0.00323%	30,996
Remaining individualsnot grpmax-eligible	0.0016%	62,374

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.Ala775Val
Coding: c.2324C>T
dbSNP: rs767408102
Type: single nucleotide variant
Location: chr5:96770586 (GRCh38)
Gene constraint: LOEUF 1.208 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 59.67

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

CAST p.Ala775= 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-ala775val (accessed [today's date]).

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