Is CAST p.Ala620Val (c.1859C>T) pathogenic?

CAST p.Ala620Val (c.1859C>T) is classified Benign in CAST (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-28). AlphaMissense: likely benign (0.1268); Low-frequency (popmax 3.94%, afr).

How common is CAST p.Ala620Val (c.1859C>T) in the general population?

CAST p.Ala620Val (c.1859C>T) is low-frequency (popmax 3.94%, afr) (gnomAD).

What do computational predictors say about CAST p.Ala620Val (c.1859C>T)?

AlphaMissense predicts likely benign (score 0.1268) — an in-silico prediction, not a clinical call.

CAST p.Ala620Val

c.1859C>T · rs4948 · VCV785131

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1268 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 3.94%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1268	likely benign
REVEL	0.088	moderately benign-leaning
SaProt	LLR -7.96	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 4.6	GERP 1.2, phastCons 1
Overall
CADD	23.4	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 A537V vs ClinVar A620V) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 3.94% African / African-American · 2,943/74,626 alleles

Filtering AF 3.82% ClinGen BA1/BS1 input FAF95, joint · FAF99 3.78%

Overall 0.206% 3,316/1,607,794 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	3.94%	25
Remaining individualsnot grpmax-eligible	0.249%	401
Admixed American	0.246%	407
Middle Eastern	0.116%	863
European (non-Finnish)	0.0056%	17,851
South Asian	0.00223%	44,908

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.Ala620Val
Coding: c.1859C>T
dbSNP: rs4948
Type: single nucleotide variant
Location: chr5:96762299 (GRCh38)
Gene constraint: LOEUF 1.208 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 59.67
Residue 620: the 'disordered' region

Full CAST gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PCSK1 p.Lys286Ter Pathogenic/Likely pathogenic ★★ same type
CAST p.Ala329Gly Uncertain significance ★★ ⚠ same type
CAST p.Asp160Val Uncertain significance ★★ ⚠ same type
CAST p.Gln731His Uncertain significance ★★ ⚠ same type
CAST p.Glu296Gly Uncertain significance ★★ ⚠ same type
CAST p.Ile274Val Uncertain significance ★★ ⚠ same type
CAST p.Leu586Pro Uncertain significance ★★ ⚠ same type
CAST p.Ser231Leu Uncertain significance ★★ ⚠ same type

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-ala620val (accessed [today's date]).

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