Is COLQ p.Pro278His (c.833C>A) pathogenic?

COLQ p.Pro278His (c.833C>A) is classified Uncertain significance in COLQ (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-03). AlphaMissense: likely benign (0.1295); Very rare (popmax 0.00134%, afr); Associated with congenital myasthenic syndrome 5.

What condition is associated with COLQ p.Pro278His (c.833C>A)?

COLQ p.Pro278His (c.833C>A) is associated with congenital myasthenic syndrome 5 (ClinVar).

How common is COLQ p.Pro278His (c.833C>A) in the general population?

COLQ p.Pro278His (c.833C>A) is very rare (popmax 0.00134%, afr) (gnomAD).

How is Congenital myasthenic syndrome inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about COLQ p.Pro278His (c.833C>A)?

AlphaMissense predicts likely benign (score 0.1295) — an in-silico prediction, not a clinical call.

COLQ p.Pro278His

c.833C>A · rs1341977323 · VCV972433

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1295 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

congenital myasthenic syndrome 5

Computational evidence

Protein change
AlphaMissense	0.1295	likely benign
REVEL	0.647	pathogenic-leaning
SaProt	LLR -10.76	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.3	GERP 0.27, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 70 kb · p 0.34 · regional, not allelic
Overall
CADD	24.3	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 0.00134% African / African-American · 1/74,886 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000248% 4/1,613,972 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00134%	74,886
European (non-Finnish)	0.000254%	393,342

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: COLQ
Protein: p.Pro278His
Coding: c.833C>A
MANE Select: NM_005677
dbSNP: rs1341977323
Type: single nucleotide variant
Location: chr3:15458307 (GRCh38)
Gene constraint: LOEUF 0.902 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 55.25 · 2 PDB
Residue 278: a UniProt-annotated variant site (in cms5; pathogenic); the collagen-like 2 domain; the 'disordered' region

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

Disease context

congenital myasthenic syndrome 5 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Congenital myasthenic syndrome (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Infancy, Neonatal
Prevalence: 1-9 / 1 000 000 (Europe)

Similar variants

COLQ p.Pro278Arg Uncertain significance ★★ ⚠ same residue
COLQ c.1195+1G>A Pathogenic ★★ same condition
COLQ c.1298+3A>G Pathogenic ★★ same condition
COLQ c.219+1G>C Pathogenic ★★ same condition
COLQ c.220-1G>A Pathogenic/Likely pathogenic ★★ same condition
COLQ c.393+1G>A Pathogenic ★★ same condition
COLQ c.529-2A>G Pathogenic/Likely pathogenic ★★ same condition
COLQ c.555+1G>A Likely pathogenic ★★ 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/colq-p-pro278his (accessed [today's date]).

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