Is CAST p.Arg550His (c.1649G>A) pathogenic?

CAST p.Arg550His (c.1649G>A) is classified Conflicting classifications of pathogenicity in CAST (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-01-17). AlphaMissense: likely benign (0.0815); Rare (popmax 0.781%, afr); Associated with Inborn genetic diseases.

What condition is associated with CAST p.Arg550His (c.1649G>A)?

CAST p.Arg550His (c.1649G>A) is associated with Inborn genetic diseases (ClinVar).

How common is CAST p.Arg550His (c.1649G>A) in the general population?

CAST p.Arg550His (c.1649G>A) is rare (popmax 0.781%, afr) (gnomAD).

What do computational predictors say about CAST p.Arg550His (c.1649G>A)?

AlphaMissense predicts likely benign (score 0.0815) — an in-silico prediction, not a clinical call.

CAST p.Arg550His

c.1649G>A · rs113315765 · VCV2226066

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0815 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.781%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0815	likely benign
REVEL	0.061	moderately benign-leaning
SaProt	LLR -9.16	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 0.62	GERP -5.1, phastCons 0.002
Overall
CADD	18.04	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 R467H vs ClinVar R550H) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.781% African / African-American · 584/74,770 alleles

Filtering AF 0.729% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.708%

Overall 0.0452% 727/1,607,712 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.781%	128
Middle Eastern	0.0829%	1,207
Remaining individualsnot grpmax-eligible	0.0723%	1,383
Admixed American	0.0686%	1,457
South Asian	0.0287%	3,483
East Asian	0.00223%	44,822
European (non-Finnish)	0.00213%	47,005

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.Arg550His
Coding: c.1649G>A
dbSNP: rs113315765
Type: single nucleotide variant
Location: chr5:96754680 (GRCh38)
Gene constraint: LOEUF 1.208 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 59.67
Residue 550: 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

CAST p.Arg550Gly Uncertain significance ★ ⚠ same residue
PCSK1 p.Asn550= Benign/Likely benign ★★ same residue
CAST p.Arg550Cys 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

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-arg550his (accessed [today's date]).

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