Is GLIS2 p.Pro66= (c.198C>T) pathogenic?

GLIS2 p.Pro66= (c.198C>T) is classified Likely benign in GLIS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-30). Very rare (popmax 0.00167%, amr).

How common is GLIS2 p.Pro66= (c.198C>T) in the general population?

GLIS2 p.Pro66= (c.198C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

GLIS2 p.Pro66=

c.198C>T · VCV3520574

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -13	GERP -4.3
Overall
CADD	0.239	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/59,988 alleles

Filtering AF 0.000803% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00065%

Overall 0.00112% 18/1,612,946 alleles · very rare exomes 16/1,460,824 · genomes 2/152,122 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	59,988
Remaining individualsnot grpmax-eligible	0.0016%	62,476
European (non-Finnish)	0.00136%	73,750

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: GLIS2
Protein: p.Pro66=
Coding: c.198C>T
MANE Select: NM_032575
Type: single nucleotide variant
Location: chr16:4333372 (GRCh38)
Gene constraint: LOEUF 0.637 · pLI 0.33 (gnomAD)
Structure: AlphaFold pLDDT 55.47
Residue 66: the 'interaction with ctnnd1' region

Full GLIS2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

GLIS2 c.*1826C>T Uncertain significance ★★ same type
GLIS2 c.*916G>A Uncertain significance ★★ same type
GLIS2 p.Ala19Val Uncertain significance ★★ ⚠ same type
GLIS2 p.Ala210Thr Uncertain significance ★★ same type
GLIS2 p.Ala360Thr Uncertain significance ★★ ⚠ same type
GLIS2 p.Ala437Thr Uncertain significance ★★ ⚠ same type
GLIS2 p.Arg102Cys Uncertain significance ★★ ⚠ same type
GLIS2 p.Arg236His 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/glis2-p-pro66 (accessed [today's date]).

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