Is CAST p.Val678fs (c.2033_2037del) pathogenic?

CAST p.Val678fs (c.20332037del) is classified Pathogenic in CAST (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-31). Very rare (popmax 0.000109%, nfe).

How common is CAST p.Val678fs (c.2033_2037del) in the general population?

CAST p.Val678fs (c.2033_2037del) is very rare (popmax 0.000109%, nfe) (gnomAD).

CAST p.Val678fs

c.2033_2037del · rs2532855985 · VCV2995747

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000109%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function; NMD-escape possible for C-terminal truncations
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 11	GERP 2, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000109% European (non-Finnish) · 1/918,960 alleles

Overall 0.000173% 2/1,155,760 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00194%	51,602
European (non-Finnish)grpmax	0.000109%	918,957

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Val678fs
Coding: c.2033_2037del
dbSNP: rs2532855985
Type: Microsatellite
Location: chr5:96765316 (GRCh38)
Gene constraint: LOEUF 1.208 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 59.67
Residue 678: the 'disordered' region

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

Similar variants

CAST p.Val678Leu Uncertain significance ★ ⚠ same residue
PCSK1 p.Asn678= Likely benign ★ same residue
CAST p.Lys121del Uncertain significance ★ same type
CAST c.1833+15_1833+16del Likely benign ★ same type
CAST c.2037+27_2037+28insTAAAAAAAAAAAAAAAAAAAAA Likely benign ★ same type
CAST c.270+237TTGTT[6] Benign ★ same type
CAST c.699+219AAAC[2] Benign ★ same type
CAST c.75+157GCAGGTGGCT[3] Benign ★ 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-val678fs (accessed [today's date]).

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