Is PYROXD1 p.Val298fs (c.892_895del) pathogenic?

PYROXD1 p.Val298fs (c.892895del) is classified Pathogenic/Likely pathogenic in PYROXD1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-04-14). Ultra-rare (popmax 0.0107%, afr); Associated with myofibrillar myopathy 8.

What condition is associated with PYROXD1 p.Val298fs (c.892_895del)?

PYROXD1 p.Val298fs (c.892_895del) is associated with myofibrillar myopathy 8 (ClinVar).

How common is PYROXD1 p.Val298fs (c.892_895del) in the general population?

PYROXD1 p.Val298fs (c.892_895del) is ultra-rare (popmax 0.0107%, afr) (gnomAD).

PYROXD1 p.Val298fs

c.892_895del · rs757103085 · VCV1452765

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0107%, afr)

Conditions

myofibrillar myopathy 8

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 9 of 12
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 1.8	GERP 1.9, phastCons 0.99
Overall
CADD	35.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0107% African / African-American · 8/74,566 alleles

Filtering AF 0.0053% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00382%

Overall 0.00286% 46/1,605,616 alleles · ultra-rare exomes 36/1,453,764 · genomes 10/151,852 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0107%	9,321
Admixed American	0.01%	9,961
Remaining individualsnot grpmax-eligible	0.00483%	20,689
Finnishnot grpmax-eligible	0.00314%	31,860
European (non-Finnish)	0.0023%	43,520

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: PYROXD1
Protein: p.Val298fs
Coding: c.892_895del
MANE Select: NM_024854
dbSNP: rs757103085
Type: Deletion
Location: chr12:21462017 (GRCh38)
Gene constraint: LOEUF 1.107 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.64 · 2 PDB
Residue 298: a β-strand

Full PYROXD1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

myofibrillar myopathy 8 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PYROXD1 p.Cys111fs Pathogenic/Likely pathogenic ★★ same condition
PYROXD1 p.Gly335del Uncertain significance ★ same condition
PYROXD1 c.285+1G>A Pathogenic/Likely pathogenic ★★ same condition
PYROXD1 p.Asn155Ser Pathogenic ★★ same condition
PYROXD1 p.Leu112fs Pathogenic ★★ same condition
PYROXD1 p.Arg132Cys Uncertain significance ★★ ⚠ same condition
PYROXD1 c.165+22G>C Benign ★★ same condition
PYROXD1 c.489-23A>G 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/pyroxd1-p-val298fs (accessed [today's date]).

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