Is GLIS3 p.Ser221Ter (c.662C>G) pathogenic?

GLIS3 p.Ser221Ter (c.662C>G) is classified Pathogenic in GLIS3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-13). Absent from gnomAD v4.1.

How common is GLIS3 p.Ser221Ter (c.662C>G) in the general population?

GLIS3 p.Ser221Ter (c.662C>G) is absent from gnomAD v4.1 (gnomAD).

GLIS3 p.Ser221Ter

c.662C>G · VCV3694326

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Absent

absent from gnomAD v4.1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 4 of 11
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 8.1	GERP 0.98, phastCons 1
Overall
CADD	35.0	PHRED · no single calibrated threshold — expert panels disagree

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

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: GLIS3
Protein: p.Ser221Ter
Coding: c.662C>G
MANE Select: NM_001042413
Type: single nucleotide variant
Location: chr9:4118816 (GRCh38)
Gene constraint: LOEUF 0.853 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 49.95

Full GLIS3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

GLIS3 c.596+6A>C Uncertain significance ★★ same type
GLIS3 c.*3330G>A Uncertain significance ★★ same type
GLIS3 c.*3344T>A Uncertain significance ★★ same type
GLIS3 c.*3920G>A Uncertain significance ★★ same type
GLIS3 c.*69T>C Uncertain significance ★★ same type
GLIS3 p.Ala233Thr Uncertain significance ★★ ⚠ same type
GLIS3 p.Ala446Val Uncertain significance ★★ ⚠ same type
GLIS3 p.Ala615Ser 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/glis3-p-ser221ter (accessed [today's date]).

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