Is CHN1 p.Arg321Thr (c.962G>C) pathogenic?

CHN1 p.Arg321Thr (c.962G>C) is classified Conflicting classifications of pathogenicity in CHN1 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-01-01). AlphaMissense: likely pathogenic (0.6913); Rare (popmax 0.132%, mid); Associated with Inborn genetic diseases.

What condition is associated with CHN1 p.Arg321Thr (c.962G>C)?

CHN1 p.Arg321Thr (c.962G>C) is associated with Inborn genetic diseases, Duane retraction syndrome 2 (ClinVar).

How common is CHN1 p.Arg321Thr (c.962G>C) in the general population?

CHN1 p.Arg321Thr (c.962G>C) is rare (popmax 0.132%, mid) (gnomAD).

What do computational predictors say about CHN1 p.Arg321Thr (c.962G>C)?

AlphaMissense predicts likely pathogenic (score 0.6913) — an in-silico prediction, not a clinical call.

CHN1 p.Arg321Thr

c.962G>C · rs202153128 · VCV931006

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.6913 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.132%, mid)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.6913	likely pathogenic
REVEL	0.143	moderately benign-leaning
SaProt	LLR -10.86	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 7.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 24 kb · p 0.00014 · regional, not allelic
Overall
CADD	32.0	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

Grpmax group 0.132% Middle Eastern · 8/6,064 alleles

Filtering AF 0.0656% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0478%

Overall 0.00753% 121/1,607,190 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.132%	758
Remaining individualsnot grpmax-eligible	0.0129%	7,778
European (non-Finnish)	0.00885%	11,297
South Asian	0.00111%	90,390

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.Arg321Thr
Coding: c.962G>C
MANE Select: NM_001822
dbSNP: rs202153128
Type: single nucleotide variant
Location: chr2:174811513 (GRCh38)
Gene constraint: LOEUF 0.79 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.41 · 2 PDB
Residue 321: the rho-gap domain; an α-helix

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Duane retraction syndrome 2

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-arg321thr (accessed [today's date]).

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