Is PYCR2 p.Val258Ala (c.773T>C) pathogenic?

PYCR2 p.Val258Ala (c.773T>C) is classified Likely pathogenic in PYCR2 (ClinVar, Single submitter, 2 submitters; last evaluated 2024-03-20). AlphaMissense: likely pathogenic (0.8377); Absent from gnomAD v4.1; Associated with leukodystrophy, hypomyelinating, 10.

What condition is associated with PYCR2 p.Val258Ala (c.773T>C)?

PYCR2 p.Val258Ala (c.773T>C) is associated with leukodystrophy, hypomyelinating, 10 (ClinVar).

How common is PYCR2 p.Val258Ala (c.773T>C) in the general population?

PYCR2 p.Val258Ala (c.773T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PYCR2 p.Val258Ala (c.773T>C)?

AlphaMissense predicts likely pathogenic (score 0.8377) — an in-silico prediction, not a clinical call.

PYCR2 p.Val258Ala

c.773T>C · rs886037932 · VCV254248

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8377 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

leukodystrophy, hypomyelinating, 10

Computational evidence

Protein change
AlphaMissense	0.8377	likely pathogenic ✓ concordant with ClinVar
REVEL	0.778	moderately pathogenic-leaning
SaProt	LLR -11.79	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>C here scores Δ0.99 · evaluated, not missing
Constraint at this position
Conservation	phyloP 11	GERP 0.87, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 3,652 bp · p 0.034 · regional, not allelic
Overall
CADD	26.1	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

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: PYCR2
Protein: p.Val258Ala
Coding: c.773T>C
MANE Select: NM_013328
dbSNP: rs886037932
Type: single nucleotide variant
Location: chr1:225921232 (GRCh38)
Gene constraint: LOEUF 1.029 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.60 · 2 PDB
Residue 258: an α-helix

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.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.Ala187Thr Uncertain significance ★★ ⚠ same condition
PYCR2 p.Arg17Pro Uncertain significance ★★ ⚠ same condition
PYCR2 c.797+14G>A Benign ★★ same condition
PYCR2 c.797+9A>C 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/pycr2-p-val258ala (accessed [today's date]).

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