Is CHN1 p.Ile352Phe (c.1054A>T) pathogenic?

CHN1 p.Ile352Phe (c.1054A>T) is classified Uncertain significance in CHN1 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-04-22). AlphaMissense: likely pathogenic (0.7942); Absent from gnomAD v4.1; Associated with Duane retraction syndrome 2.

What condition is associated with CHN1 p.Ile352Phe (c.1054A>T)?

CHN1 p.Ile352Phe (c.1054A>T) is associated with Duane retraction syndrome 2 (ClinVar).

How common is CHN1 p.Ile352Phe (c.1054A>T) in the general population?

CHN1 p.Ile352Phe (c.1054A>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CHN1 p.Ile352Phe (c.1054A>T)?

AlphaMissense predicts likely pathogenic (score 0.7942) — an in-silico prediction, not a clinical call.

CHN1 p.Ile352Phe

c.1054A>T · VCV4820645

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7942 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Duane retraction syndrome 2

Computational evidence

Protein change
AlphaMissense	0.7942	likely pathogenic
REVEL	0.222	benign-leaning
SaProt	LLR -11.36	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.2	GERP 1.9, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 24 kb · p 0.00014 · regional, not allelic
Overall
CADD	28.1	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CHN1
Protein: p.Ile352Phe
Coding: c.1054A>T
MANE Select: NM_001822
Type: single nucleotide variant
Location: chr2:174808953 (GRCh38)
Gene constraint: LOEUF 0.79 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.41 · 2 PDB
Residue 352: 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-ile352phe (accessed [today's date]).

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