Is CAST p.Thr261Pro (c.781A>C) pathogenic?

CAST p.Thr261Pro (c.781A>C) is classified Uncertain significance in CAST (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-11). AlphaMissense: likely benign (0.2523); Very rare (popmax 8.64e-05%, nfe); Associated with Inborn genetic diseases.

What condition is associated with CAST p.Thr261Pro (c.781A>C)?

CAST p.Thr261Pro (c.781A>C) is associated with Inborn genetic diseases (ClinVar).

How common is CAST p.Thr261Pro (c.781A>C) in the general population?

CAST p.Thr261Pro (c.781A>C) is very rare (popmax 8.64e-05%, nfe) (gnomAD).

What do computational predictors say about CAST p.Thr261Pro (c.781A>C)?

AlphaMissense predicts likely benign (score 0.2523) — an in-silico prediction, not a clinical call.

CAST p.Thr261Pro

c.781A>C · VCV4219533

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2523 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.64e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2523	likely benign
REVEL	0.17	moderately benign-leaning
SaProt	LLR -7.82	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>G here scores Δ0.39 · evaluated, not missing
Constraint at this position
Conservation	phyloP 2.6	GERP -0.04, phastCons 0.86
Overall
CADD	21.3	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 T178P vs ClinVar T261P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.64e-05% European (non-Finnish) · 1/1,157,910 alleles

Overall 6.96e-05% 1/1,437,150 alleles · very rare

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.Thr261Pro
Coding: c.781A>C
Type: single nucleotide variant
Location: chr5:96737930 (GRCh38)
Gene constraint: LOEUF 1.208 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 59.67
Residue 261: 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.Val261Met Uncertain significance ⚠ 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-thr261pro (accessed [today's date]).

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