Is GLE1 p.Pro2Arg (c.5C>G) pathogenic?

GLE1 p.Pro2Arg (c.5C>G) is classified Conflicting classifications of pathogenicity in GLE1 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-02-02). AlphaMissense: likely benign (0.1917); Rare (popmax 0.694%, mid); Associated with lethal arthrogryposis-anterior horn cell disease syndrome.

How common is GLE1 p.Pro2Arg (c.5C>G) in the general population?

GLE1 p.Pro2Arg (c.5C>G) is rare (popmax 0.694%, mid) (gnomAD).

What do computational predictors say about GLE1 p.Pro2Arg (c.5C>G)?

AlphaMissense predicts likely benign (score 0.1917) — an in-silico prediction, not a clinical call.

GLE1 p.Pro2Arg

Q: What condition is associated with GLE1 p.Pro2Arg (c.5C>G)?

GLE1 p.Pro2Arg (c.5C>G) is associated with lethal arthrogryposis-anterior horn cell disease syndrome, lethal congenital contracture syndrome 1 (ClinVar).

c.5C>G · rs150246404 · VCV285426

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.1917 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.694%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

lethal arthrogryposis-anterior horn cell disease syndrome

Computational evidence

Protein change
AlphaMissense	0.1917	likely benign
REVEL	0.269	benign-leaning
SaProt	LLR -6.14	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 3.7	GERP 0.88, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 36 kb · p 0.00036 · regional, not allelic
Overall
CADD	25.4	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.694% Middle Eastern · 42/6,054 alleles

Filtering AF 0.528% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.469%

Overall 0.0695% 1,116/1,605,856 alleles · rare exomes 994/1,453,518 · genomes 122/152,338 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.694%	144
South Asian	0.17%	587
Admixed American	0.168%	594
Ashkenazi Jewishnot grpmax-eligible	0.101%	985
Remaining individualsnot grpmax-eligible	0.0852%	1,174
European (non-Finnish)	0.0611%	1,638
Finnishnot grpmax-eligible	0.0219%	4,566
African / African-American	0.00668%	14,976

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: GLE1
Protein: p.Pro2Arg
Coding: c.5C>G
MANE Select: NM_001003722
dbSNP: rs150246404
Type: single nucleotide variant
Location: chr9:128504810 (GRCh38)
Gene constraint: LOEUF 1.103 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.55 · 3 PDB
Residue 2: the 'interaction with nup155' region

Full GLE1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

lethal arthrogryposis-anterior horn cell disease syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: lethal congenital contracture syndrome 1

Similar variants

GLE1 p.Pro2= Likely benign ★ same residue
GLE1 c.1881+1G>T Likely pathogenic ★★ same condition
GLE1 c.2029-1G>A Likely pathogenic ★★ same condition
GLE1 c.433-10A>G Pathogenic ★★ same condition
GLE1 p.Arg133Ter Pathogenic/Likely pathogenic ★★ same condition
GLE1 p.Arg569His Pathogenic/Likely pathogenic ★★ same condition
GLE1 p.Arg584Trp Pathogenic/Likely pathogenic ★★ ⚠ same condition
GLE1 p.Gln81Ter Pathogenic/Likely pathogenic ★★ 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/gle1-p-pro2arg (accessed [today's date]).

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