Is CHN1 p.Pro252Gln (c.755C>A) pathogenic?

CHN1 p.Pro252Gln (c.755C>A) is classified Pathogenic in CHN1 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2008-08-08). AlphaMissense: likely pathogenic (0.7671); Absent from gnomAD v4.1; Associated with Duane retraction syndrome 2.

What condition is associated with CHN1 p.Pro252Gln (c.755C>A)?

CHN1 p.Pro252Gln (c.755C>A) is associated with Duane retraction syndrome 2 (ClinVar).

How common is CHN1 p.Pro252Gln (c.755C>A) in the general population?

CHN1 p.Pro252Gln (c.755C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CHN1 p.Pro252Gln (c.755C>A)?

AlphaMissense predicts likely pathogenic (score 0.7671) — an in-silico prediction, not a clinical call.

CHN1 p.Pro252Gln

c.755C>A · rs121912797 · VCV17555

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7671 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Duane retraction syndrome 2

Computational evidence

Protein change
AlphaMissense	0.7671	likely pathogenic ✓ concordant with ClinVar
REVEL	0.833	moderately pathogenic-leaning
SaProt	LLR -14.62	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 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 24 kb · p 0.00014 · regional, not allelic
Overall
CADD	31.0	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.Pro252Gln
Coding: c.755C>A
MANE Select: NM_001822
dbSNP: rs121912797
Type: single nucleotide variant
Location: chr2:174812440 (GRCh38)
Gene constraint: LOEUF 0.79 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.41 · 2 PDB
Residue 252: a UniProt-annotated variant site (in durs2; behaves as a dominant gain-of-function allele that increases chn1 activity in vitro; appears to enhance membrane translocation and chn1 activity by destabilizing the closed conformation of chn1 protein in response to phorbol 12-myristate 13-acetate (pma))

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.Pro252Ser 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-pro252gln (accessed [today's date]).

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