Is CHN1 p.Glu334= (c.1002A>G) pathogenic?

CHN1 p.Glu334= (c.1002A>G) is classified Uncertain significance in CHN1 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-12). Ultra-rare (popmax 0.0416%, nfe); Associated with Duane retraction syndrome 2.

What condition is associated with CHN1 p.Glu334= (c.1002A>G)?

CHN1 p.Glu334= (c.1002A>G) is associated with Duane retraction syndrome 2 (ClinVar).

How common is CHN1 p.Glu334= (c.1002A>G) in the general population?

CHN1 p.Glu334= (c.1002A>G) is ultra-rare (popmax 0.0416%, nfe) (gnomAD).

CHN1 p.Glu334=

c.1002A>G · rs376051698 · VCV893849

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0416%, nfe)

Conditions

Duane retraction syndrome 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>A here scores Δ0.23 · evaluated, not missing
Constraint at this position
Conservation	phyloP 2.4	GERP 1.9, phastCons 1
Overall
CADD	6.936	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0416% European (non-Finnish) · 490/1,178,776 alleles

Filtering AF 0.0385% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0373%

Overall 0.0317% 511/1,610,810 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0416%	2,406
Remaining individualsnot grpmax-eligible	0.0144%	6,930
Admixed American	0.0101%	9,927
African / African-American	0.00668%	14,975
Finnishnot grpmax-eligible	0.00156%	64,008

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: CHN1
Protein: p.Glu334=
Coding: c.1002A>G
MANE Select: NM_001822
dbSNP: rs376051698
Type: single nucleotide variant
Location: chr2:174809005 (GRCh38)
Gene constraint: LOEUF 0.79 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.41 · 2 PDB
Residue 334: the rho-gap domain

Full CHN1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Duane retraction syndrome 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CHN1 c.-160C>G Uncertain significance ★★ same condition
CHN1 c.-74C>T Uncertain significance ★★ same condition
CHN1 p.Ala27Gly Uncertain significance ★★ ⚠ same condition
CHN1 p.Asp440Gly Uncertain significance ★★ ⚠ same condition
CHN1 p.Lys260Asn Uncertain significance ★★ ⚠ same condition
CHN1 p.Thr167Ile Uncertain significance ★★ ⚠ same condition
CHN1 p.Val65Met Uncertain significance ★★ ⚠ same condition
CHN1 c.886+15G>A 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/chn1-p-glu334 (accessed [today's date]).

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