Is GLIS3 p.Pro255Arg (c.764C>G) pathogenic?

GLIS3 p.Pro255Arg (c.764C>G) is classified Uncertain significance in GLIS3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-07). AlphaMissense: likely benign (0.2627); Very rare (popmax 0.005%, amr); Associated with Inborn genetic diseases.

What condition is associated with GLIS3 p.Pro255Arg (c.764C>G)?

GLIS3 p.Pro255Arg (c.764C>G) is associated with Inborn genetic diseases (ClinVar).

How common is GLIS3 p.Pro255Arg (c.764C>G) in the general population?

GLIS3 p.Pro255Arg (c.764C>G) is very rare (popmax 0.005%, amr) (gnomAD).

What do computational predictors say about GLIS3 p.Pro255Arg (c.764C>G)?

AlphaMissense predicts likely benign (score 0.2627) — an in-silico prediction, not a clinical call.

GLIS3 p.Pro255Arg

c.764C>G · VCV4620909

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2627 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2627	likely benign
REVEL	0.087	moderately benign-leaning
SaProt	LLR -7.52	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 12	GERP 2.1, phastCons 1
Regional constraint	o/e 1.38	unconstrained · MANE · 458 kb · p 3.1e-41 · regional, not allelic
Overall
CADD	24.4	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P100R vs ClinVar P255R) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.005% Admixed American · 3/59,988 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.000496% 8/1,613,974 alleles · very rare exomes 6/1,461,876 · genomes 2/152,098 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.005%	19,996
European (non-Finnish)	0.000424%	236,007

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: GLIS3
Protein: p.Pro255Arg
Coding: c.764C>G
MANE Select: NM_001042413
Type: single nucleotide variant
Location: chr9:4118714 (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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

GLIS3 p.Pro255His Uncertain significance ★★ ⚠ same residue
GLIS3 p.Ala233Thr Uncertain significance ★★ ⚠ same condition
GLIS3 p.Ala784Pro Uncertain significance ★★ ⚠ same condition
GLIS3 p.Arg637Cys Uncertain significance ★★ ⚠ same condition
GLIS3 p.Arg663Gln Uncertain significance ★★ ⚠ same condition
GLIS3 p.Asp310Asn Uncertain significance ★★ ⚠ same condition
GLIS3 p.Cys676Phe Uncertain significance ★★ same condition
GLIS3 p.Gly385Ser 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/glis3-p-pro255arg (accessed [today's date]).

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