Is PYCR2 p.Asp85fs (c.252del) pathogenic?

PYCR2 p.Asp85fs (c.252del) is classified Pathogenic/Likely pathogenic in PYCR2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-07-10). Very rare (popmax 0.000339%, nfe); Associated with leukodystrophy, hypomyelinating, 10.

What condition is associated with PYCR2 p.Asp85fs (c.252del)?

PYCR2 p.Asp85fs (c.252del) is associated with leukodystrophy, hypomyelinating, 10 (ClinVar).

How common is PYCR2 p.Asp85fs (c.252del) in the general population?

PYCR2 p.Asp85fs (c.252del) is very rare (popmax 0.000339%, nfe) (gnomAD).

PYCR2 p.Asp85fs

c.252del · rs35240460 · VCV1905643

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Conditions

leukodystrophy, hypomyelinating, 10

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 3 of 7
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 4.8	GERP -0.45, phastCons 1

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000339% European (non-Finnish) · 4/1,180,036 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000248% 4/1,614,220 alleles · very rare exomes 4/1,461,876 · genomes 0/152,344 · joint denominator

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: PYCR2
Protein: p.Asp85fs
Coding: c.252del
MANE Select: NM_013328
dbSNP: rs35240460
Type: Deletion
Location: chr1:225922270 (GRCh38)
Gene constraint: LOEUF 1.029 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.60 · 2 PDB
Residue 85: a turn

Full PYCR2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

leukodystrophy, hypomyelinating, 10 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PYCR2 p.Val104fs Pathogenic/Likely pathogenic ★★ same condition
PYCR2 p.Thr133fs Likely pathogenic ★ same condition
PYCR2 p.Arg119Cys Pathogenic/Likely pathogenic ★★ same condition
PYCR2 p.Arg119His Likely pathogenic ★★ same condition
PYCR2 p.Arg266Ter Pathogenic ★★ same condition
PYCR2 p.Gln226Ter Pathogenic/Likely pathogenic ★★ same condition
PYCR2 p.Leu254fs Pathogenic/Likely pathogenic ★★ same condition
PYCR2 p.Ala187Thr 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/pycr2-p-asp85fs (accessed [today's date]).

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