Is CHRND p.Thr321Pro (c.961A>C) pathogenic?

CHRND p.Thr321Pro (c.961A>C) is classified Uncertain significance in CHRND (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-15). AlphaMissense: likely pathogenic (0.6475); Absent from gnomAD v4.1; Associated with congenital myasthenic syndrome 3B.

What condition is associated with CHRND p.Thr321Pro (c.961A>C)?

CHRND p.Thr321Pro (c.961A>C) is associated with congenital myasthenic syndrome 3B (ClinVar).

How common is CHRND p.Thr321Pro (c.961A>C) in the general population?

CHRND p.Thr321Pro (c.961A>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CHRND p.Thr321Pro (c.961A>C)?

AlphaMissense predicts likely pathogenic (score 0.6475) — an in-silico prediction, not a clinical call.

CHRND p.Thr321Pro

c.961A>C · rs2469727678 · VCV1709700

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6475 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

congenital myasthenic syndrome 3B

Computational evidence

Protein change
AlphaMissense	0.6475	likely pathogenic
REVEL	0.698	pathogenic-leaning
SaProt	LLR -12.52	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 -0.14	GERP -4.3
Regional constraint	o/e 0.94	unconstrained · MANE · 9,093 bp · p 0.12 · regional, not allelic
Overall
CADD	19.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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: CHRND
Protein: p.Thr321Pro
Coding: c.961A>C
MANE Select: NM_000751
dbSNP: rs2469727678
Type: single nucleotide variant
Location: chr2:232531570 (GRCh38)
Gene constraint: LOEUF 0.848 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.21 · 25 PDB
Residue 321: an α-helix

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

Disease context

congenital myasthenic syndrome 3B — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CHRND p.Thr321Asn Uncertain significance ★ ⚠ same residue
CHRND p.Thr321Ile Uncertain significance ★ ⚠ same residue
CHRND p.Trp78Ter Pathogenic ★★ same condition
CHRND p.Trp83Ter Pathogenic/Likely pathogenic ★★ same condition
CHRND p.Arg233Cys Uncertain significance ★★ ⚠ same condition
CHRND p.Arg27Gln Uncertain significance ★★ ⚠ same condition
CHRND p.Arg407Gln Uncertain significance ★★ ⚠ same condition
CHRND p.Asp201Asn 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/chrnd-p-thr321pro (accessed [today's date]).

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