Is CAST p.Lys165= (c.495A>G) pathogenic?

CAST p.Lys165= (c.495A>G) is classified Likely benign in CAST (ClinVar, No assertion criteria, 1 submitter; last evaluated 2020-06-01). Absent from gnomAD v4.1; Associated with CAST-related disorder.

What condition is associated with CAST p.Lys165= (c.495A>G)?

CAST p.Lys165= (c.495A>G) is associated with CAST-related disorder (ClinVar).

How common is CAST p.Lys165= (c.495A>G) in the general population?

CAST p.Lys165= (c.495A>G) is absent from gnomAD v4.1 (gnomAD).

CAST p.Lys165=

c.495A>G · rs1760047816 · VCV3036793

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

CAST-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.043	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.7	GERP -1.9, phastCons 1
Overall
CADD	6.691	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CAST
Protein: p.Lys165=
Coding: c.495A>G
dbSNP: rs1760047816
Type: single nucleotide variant
Location: chr5:96729671 (GRCh38)
Gene constraint: LOEUF 1.208 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 59.67
Residue 165: the 'disordered' region

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

Disease context

CAST-related disorder

Similar variants

CAST p.Lys165Asn Uncertain significance ★ ⚠ same residue
PCSK1 p.Ala368Thr Uncertain significance ★★ ⚠ same condition
PCSK1 p.Asp193Gly Uncertain significance ★★ ⚠ same condition
CAST p.Gln499Ter Likely pathogenic ★ same condition
CAST p.Glu568Ter Likely pathogenic ★ same condition
PCSK1 p.Asn423Lys Likely pathogenic ★ ⚠ same condition
PCSK1 p.Asn122Ser Uncertain significance ★ ⚠ same condition
PCSK1 p.Ile156Thr 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-lys165 (accessed [today's date]).

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