Is MYBPC1 p.Gln467Glu (c.1399C>G) pathogenic?

MYBPC1 p.Gln467Glu (c.1399C>G) is classified Conflicting classifications of pathogenicity in MYBPC1 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2023-02-13). AlphaMissense: likely benign (0.1209); Ultra-rare (popmax 0.014%, nfe); Associated with arthrogryposis, distal, type 1B.

What condition is associated with MYBPC1 p.Gln467Glu (c.1399C>G)?

MYBPC1 p.Gln467Glu (c.1399C>G) is associated with arthrogryposis, distal, type 1B, lethal congenital contracture syndrome 4, myopathy, congenital, with tremor (ClinVar).

How common is MYBPC1 p.Gln467Glu (c.1399C>G) in the general population?

MYBPC1 p.Gln467Glu (c.1399C>G) is ultra-rare (popmax 0.014%, nfe) (gnomAD).

What do computational predictors say about MYBPC1 p.Gln467Glu (c.1399C>G)?

AlphaMissense predicts likely benign (score 0.1209) — an in-silico prediction, not a clinical call.

MYBPC1 p.Gln467Glu

c.1399C>G · rs146314887 · VCV882507

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1209 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.014%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

arthrogryposis, distal, type 1B

Computational evidence

Protein change
AlphaMissense	0.1209	likely benign
REVEL	0.145	moderately benign-leaning
SaProt	LLR -8.26	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.5	GERP 2.8, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 53 kb · p 6e-11 · regional, not allelic
Overall
CADD	22.5	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM Q442E vs ClinVar Q467E) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.014% European (non-Finnish) · 165/1,179,982 alleles

Filtering AF 0.0122% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0116%

Overall 0.0108% 174/1,613,924 alleles · ultra-rare

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	0.548%	182
European (non-Finnish)grpmax	0.014%	7,151
Remaining individualsnot grpmax-eligible	0.0048%	20,829
African / African-American	0.00134%	74,884

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: MYBPC1
Protein: p.Gln467Glu
Coding: c.1399C>G
MANE Select: NM_002465
dbSNP: rs146314887
Type: single nucleotide variant
Location: chr12:101651266 (GRCh38)
Gene constraint: LOEUF 0.433 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 81.99 · 8 PDB
Residue 467: the ig-like c2-type 4 domain

Full MYBPC1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

arthrogryposis, distal, type 1B — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: lethal congenital contracture syndrome 4 myopathy, congenital, with tremor

Similar variants

MYBPC1 p.Gln467Lys Uncertain significance ★ ⚠ same residue
MYBPC1 p.Arg265Gly Likely pathogenic ★★ ⚠ same condition
MYBPC1 p.Glu248Lys Pathogenic/Likely pathogenic ★★ ⚠ same condition
MYBPC1 p.Leu259Pro Pathogenic/Likely pathogenic ★★ same condition
MYBPC1 p.Leu263Arg Pathogenic ★★ same condition
MYBPC1 p.Arg146Gln Uncertain significance ★★ ⚠ same condition
MYBPC1 p.Arg718His Uncertain significance ★★ ⚠ same condition
MYBPC1 p.Gly261Ser 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/mybpc1-p-gln467glu (accessed [today's date]).

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