Is GLIS2 p.Pro405Ser (c.1213C>T) pathogenic?

GLIS2 p.Pro405Ser (c.1213C>T) is classified Uncertain significance in GLIS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-13). AlphaMissense: likely benign (0.0796); Very rare (popmax 0.00238%, sas).

How common is GLIS2 p.Pro405Ser (c.1213C>T) in the general population?

GLIS2 p.Pro405Ser (c.1213C>T) is very rare (popmax 0.00238%, sas) (gnomAD).

What do computational predictors say about GLIS2 p.Pro405Ser (c.1213C>T)?

AlphaMissense predicts likely benign (score 0.0796) — an in-silico prediction, not a clinical call.

GLIS2 p.Pro405Ser

c.1213C>T · VCV4672183

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0796 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00238%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0796	likely benign
REVEL	0.131	moderately benign-leaning
SaProt	LLR -6.82	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.9	GERP 1.7, phastCons 1
Regional constraint	o/e 1.12	unconstrained · MANE · 624 bp · p 0.045 · regional, not allelic
Overall
CADD	13.59	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 0.00238% South Asian · 2/83,996 alleles

Filtering AF 0.000395% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000148%

Overall 0.000389% 6/1,540,498 alleles · very rare exomes 5/1,388,286 · genomes 1/152,212 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00238%	41,998
Admixed American	0.00196%	50,994
African / African-American	0.00137%	72,994
European (non-Finnish)	0.000174%	573,418

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.Pro405Ser
Coding: c.1213C>T
MANE Select: NM_032575
Type: single nucleotide variant
Location: chr16:4337162 (GRCh38)
Gene constraint: LOEUF 0.637 · pLI 0.33 (gnomAD)
Structure: AlphaFold pLDDT 55.47

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

Similar variants

GLIS2 p.Pro405Thr Uncertain significance ★ ⚠ same residue
GLIS2 p.Pro405= Likely benign ★ 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

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-pro405ser (accessed [today's date]).

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