Is CHN1 p.Tyr99= (c.297C>T) pathogenic?

CHN1 p.Tyr99= (c.297C>T) is classified Uncertain significance in CHN1 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-12). Ultra-rare (popmax 0.0168%, mid); Associated with Duane retraction syndrome 2.

What condition is associated with CHN1 p.Tyr99= (c.297C>T)?

CHN1 p.Tyr99= (c.297C>T) is associated with Duane retraction syndrome 2 (ClinVar).

How common is CHN1 p.Tyr99= (c.297C>T) in the general population?

CHN1 p.Tyr99= (c.297C>T) is ultra-rare (popmax 0.0168%, mid) (gnomAD).

CHN1 p.Tyr99=

c.297C>T · rs35358913 · VCV894767

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0168%, mid)

Conditions

Duane retraction syndrome 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 10	GERP 1.9, phastCons 1
Overall
CADD	15.44	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0168% Middle Eastern · 1/5,962 alleles

Filtering AF 0.00135% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000673%

Overall 0.00132% 21/1,590,174 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0168%	5,962
Admixed American	0.00507%	19,735
East Asian	0.00225%	44,418
Remaining individualsnot grpmax-eligible	0.00163%	61,382
African / African-American	0.00134%	74,566
European (non-Finnish)	0.0012%	83,243

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.Tyr99=
Coding: c.297C>T
MANE Select: NM_001822
dbSNP: rs35358913
Type: single nucleotide variant
Location: chr2:174878092 (GRCh38)
Gene constraint: LOEUF 0.79 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.41 · 2 PDB
Residue 99: the sh2 domain; a β-strand

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 p.Tyr99His Uncertain significance ★ ⚠ same residue
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

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-tyr99 (accessed [today's date]).

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