Is GNAT2 p.Arg86Pro (c.257G>C) pathogenic?

GNAT2 p.Arg86Pro (c.257G>C) is classified Uncertain significance in GNAT2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-01-13). AlphaMissense: likely pathogenic (0.9465); Ultra-rare (popmax 0.0153%, nfe); Associated with inherited retinal dystrophy.

What condition is associated with GNAT2 p.Arg86Pro (c.257G>C)?

GNAT2 p.Arg86Pro (c.257G>C) is associated with inherited retinal dystrophy (ClinVar).

How common is GNAT2 p.Arg86Pro (c.257G>C) in the general population?

GNAT2 p.Arg86Pro (c.257G>C) is ultra-rare (popmax 0.0153%, nfe) (gnomAD).

What do computational predictors say about GNAT2 p.Arg86Pro (c.257G>C)?

AlphaMissense predicts likely pathogenic (score 0.9465) — an in-silico prediction, not a clinical call.

GNAT2 p.Arg86Pro

c.257G>C · rs140250745 · VCV1036717

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9465 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0153%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

inherited retinal dystrophy

Computational evidence

Protein change
AlphaMissense	0.9465	likely pathogenic
REVEL	0.839	moderately pathogenic-leaning
SaProt	LLR -15.44	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.4	GERP -0.8, phastCons 0.82
Regional constraint	o/e 0.82	unconstrained · MANE · 9,513 bp · p 0.00023 · regional, not allelic
Overall
CADD	23.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0153% European (non-Finnish) · 180/1,179,836 alleles

Filtering AF 0.0134% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0127%

Overall 0.0116% 187/1,613,798 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0153%	6,555
Finnishnot grpmax-eligible	0.00625%	16,008
African / African-American	0.00267%	37,439
Remaining individualsnot grpmax-eligible	0.0016%	62,476

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: GNAT2
Protein: p.Arg86Pro
Coding: c.257G>C
MANE Select: NM_001377295
dbSNP: rs140250745
Type: single nucleotide variant
Location: chr1:109610086 (GRCh38)
Gene constraint: LOEUF 1.176 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.21 · 2 PDB
Residue 86: the g-alpha domain

Full GNAT2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

inherited retinal dystrophy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

GNAT2 p.Arg86Trp Likely benign ★★ same residue
GNAT2 p.Arg86Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
GNAT2 p.Gln58Ter Pathogenic/Likely pathogenic ★★ same condition
GNAT2 p.Arg242Cys Uncertain significance ★★ ⚠ same condition
GNAT2 p.Met198Lys Likely pathogenic ★ same condition
GNAT2 p.Arg242His Uncertain significance ★ ⚠ same condition
GNAT2 p.Val124Met Conflicting classifications of pathogenicity ★ ⚠ same condition
GNAT2 p.Leu168fs 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/gnat2-p-arg86pro (accessed [today's date]).

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