Is GLIS2 p.Pro92Ser (c.274C>T) pathogenic?

GLIS2 p.Pro92Ser (c.274C>T) is classified Uncertain significance in GLIS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-15). AlphaMissense: likely benign (0.1191); Very rare (popmax 0.00935%, afr).

How common is GLIS2 p.Pro92Ser (c.274C>T) in the general population?

GLIS2 p.Pro92Ser (c.274C>T) is very rare (popmax 0.00935%, afr) (gnomAD).

What do computational predictors say about GLIS2 p.Pro92Ser (c.274C>T)?

AlphaMissense predicts likely benign (score 0.1191) — an in-silico prediction, not a clinical call.

GLIS2 p.Pro92Ser

c.274C>T · rs982313905 · VCV1706240

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1191 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00935%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1191	likely benign
REVEL	0.17	moderately benign-leaning
SaProt	LLR -5.56	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.7	GERP 2.2, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 2,809 bp · p 0.37 · regional, not allelic
Overall
CADD	21.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00935% African / African-American · 7/74,898 alleles

Filtering AF 0.00437% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00309%

Overall 0.00105% 17/1,612,816 alleles · very rare exomes 10/1,460,684 · genomes 7/152,132 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00935%	10,700
Admixed American	0.00667%	14,999
Remaining individualsnot grpmax-eligible	0.0048%	20,824
European (non-Finnish)	0.000254%	393,324

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.Pro92Ser
Coding: c.274C>T
MANE Select: NM_032575
dbSNP: rs982313905
Type: single nucleotide variant
Location: chr16:4333448 (GRCh38)
Gene constraint: LOEUF 0.637 · pLI 0.33 (gnomAD)
Structure: AlphaFold pLDDT 55.47
Residue 92: the 'interaction with ctnnd1' region; the 'transcription activation' region; the 'disordered' region

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

Similar variants

GLIS2 p.Pro92Leu Uncertain significance ★★ ⚠ same residue
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

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-pro92ser (accessed [today's date]).

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