Is CAST p.Pro713Arg (c.2138C>G) pathogenic?

CAST p.Pro713Arg (c.2138C>G) is classified Uncertain significance in CAST (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-20). AlphaMissense: likely benign (0.1218); Ultra-rare (popmax 0.0206%, nfe); Associated with Inborn genetic diseases.

What condition is associated with CAST p.Pro713Arg (c.2138C>G)?

CAST p.Pro713Arg (c.2138C>G) is associated with Inborn genetic diseases (ClinVar).

How common is CAST p.Pro713Arg (c.2138C>G) in the general population?

CAST p.Pro713Arg (c.2138C>G) is ultra-rare (popmax 0.0206%, nfe) (gnomAD).

What do computational predictors say about CAST p.Pro713Arg (c.2138C>G)?

AlphaMissense predicts likely benign (score 0.1218) — an in-silico prediction, not a clinical call.

CAST p.Pro713Arg

c.2138C>G · rs376749892 · VCV3137695

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1218 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0206%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1218	likely benign
REVEL	0.335	indeterminate
SaProt	LLR -10.96	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.6	GERP 1.2, phastCons 0.98
Overall
CADD	25.3	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 P630R vs ClinVar P713R) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0206% European (non-Finnish) · 243/1,178,460 alleles

Filtering AF 0.0184% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0176%

Overall 0.0163% 262/1,612,114 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0206%	4,850
Remaining individualsnot grpmax-eligible	0.0192%	5,202
Finnishnot grpmax-eligible	0.00469%	21,321
African / African-American	0.00267%	37,488
Admixed American	0.00167%	59,952
South Asian	0.0011%	91,032

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.Pro713Arg
Coding: c.2138C>G
dbSNP: rs376749892
Type: single nucleotide variant
Location: chr5:96767445 (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

PCSK1 p.Leu713Phe 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-pro713arg (accessed [today's date]).

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