Is CAST p.Arg393His (c.1178G>A) pathogenic?

CAST p.Arg393His (c.1178G>A) is classified Conflicting classifications of pathogenicity in CAST (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-08-26). AlphaMissense: likely benign (0.0707); Rare (popmax 0.395%, afr); Associated with Inborn genetic diseases.

What condition is associated with CAST p.Arg393His (c.1178G>A)?

CAST p.Arg393His (c.1178G>A) is associated with Inborn genetic diseases (ClinVar).

How common is CAST p.Arg393His (c.1178G>A) in the general population?

CAST p.Arg393His (c.1178G>A) is rare (popmax 0.395%, afr) (gnomAD).

What do computational predictors say about CAST p.Arg393His (c.1178G>A)?

AlphaMissense predicts likely benign (score 0.0707) — an in-silico prediction, not a clinical call.

CAST p.Arg393His

c.1178G>A · rs139285603 · VCV790564

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0707 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.395%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0707	likely benign
REVEL	0.089	moderately benign-leaning
SaProt	LLR -6.29	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 7.5	GERP 0.91, phastCons 1
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 R310H vs ClinVar R393H) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.395% African / African-American · 296/75,004 alleles

Filtering AF 0.358% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.343%

Overall 0.025% 403/1,613,306 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.395%	253
Ashkenazi Jewishnot grpmax-eligible	0.122%	822
Admixed American	0.0533%	1,875
Remaining individualsnot grpmax-eligible	0.0288%	3,471
Middle Eastern	0.0165%	6,062
South Asian	0.00659%	15,178
European (non-Finnish)	0.00119%	84,239

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.Arg393His
Coding: c.1178G>A
dbSNP: rs139285603
Type: single nucleotide variant
Location: chr5:96742734 (GRCh38)
Gene constraint: LOEUF 1.208 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 59.67
Residue 393: 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.Ala393= Benign/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-arg393his (accessed [today's date]).

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