Is GCNT2 p.Pro85Arg (c.254C>G) pathogenic?

GCNT2 p.Pro85Arg (c.254C>G) is classified Conflicting classifications of pathogenicity in GCNT2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-09-19). Rare (popmax 0.313%, mid); Associated with cataract 13 with adult I phenotype.

What condition is associated with GCNT2 p.Pro85Arg (c.254C>G)?

GCNT2 p.Pro85Arg (c.254C>G) is associated with cataract 13 with adult I phenotype (ClinVar).

How common is GCNT2 p.Pro85Arg (c.254C>G) in the general population?

GCNT2 p.Pro85Arg (c.254C>G) is rare (popmax 0.313%, mid) (gnomAD).

How is Early onset non-syndromic cataract inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

GCNT2 p.Pro85Arg

c.254C>G · rs17637756 · VCV354701

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

rare (popmax 0.313%, mid)

Conditions

cataract 13 with adult I phenotype

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.254	benign-leaning
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.4	GERP 1.7, phastCons 1
Regional constraint	o/e 1.19	unconstrained · MANE · 98 kb · p 1.9e-05 · regional, not allelic
Overall
CADD	19.51	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.313% Middle Eastern · 19/6,062 alleles

Filtering AF 0.205% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.186%

Overall 0.158% 2,552/1,614,146 alleles · rare exomes 2,401/1,461,836 · genomes 151/152,310 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.313%	319
European (non-Finnish)	0.195%	512
Remaining individualsnot grpmax-eligible	0.157%	638
Admixed American	0.132%	760
African / African-American	0.0466%	2,144
Finnishnot grpmax-eligible	0.0109%	9,147
South Asian	0.00878%	11,386
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,606

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: GCNT2
Protein: p.Pro85Arg
Coding: c.254C>G
MANE Select: NM_145649 · reported on NM_001491
dbSNP: rs17637756
Type: single nucleotide variant
Location: chr6:10556677 (GRCh38)
Gene constraint: LOEUF 1.369 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.66

Full GCNT2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

cataract 13 with adult I phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Early onset non-syndromic cataract (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, X-linked recessive
Onset: Infancy, Neonatal

Similar variants

GCNT2 p.Tyr349Cys Pathogenic/Likely pathogenic ★★ same condition
GCNT2 p.Lys135Glu Uncertain significance ★★ same condition
GCNT2 p.Val232Ile Uncertain significance ★★ ⚠ same condition
GCNT2 c.926-34546C>G Benign ★★ same condition
GCNT2 c.926-34857G>A Benign/Likely benign ★★ same condition
GCNT2 p.Ala247= Benign ★★ same condition
GCNT2 p.Arg110= Benign ★★ same condition
GCNT2 p.Arg173Gly Benign ★★ 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/gcnt2-p-pro85arg (accessed [today's date]).

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