Is PYGL p.Asp422Val (c.1265A>T) pathogenic?

PYGL p.Asp422Val (c.1265A>T) is classified Uncertain significance in PYGL (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-14). AlphaMissense: likely pathogenic (0.7215); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with PYGL p.Asp422Val (c.1265A>T)?

PYGL p.Asp422Val (c.1265A>T) is associated with Inborn genetic diseases (ClinVar).

How common is PYGL p.Asp422Val (c.1265A>T) in the general population?

PYGL p.Asp422Val (c.1265A>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PYGL p.Asp422Val (c.1265A>T)?

AlphaMissense predicts likely pathogenic (score 0.7215) — an in-silico prediction, not a clinical call.

PYGL p.Asp422Val

c.1265A>T · VCV4628719

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7215 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.7215	likely pathogenic
REVEL	0.944	strongly pathogenic-leaning
SaProt	LLR -17.47	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>C here scores Δ0.33 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.8	GERP 1.9, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 39 kb · p 0.2 · regional, not allelic
Overall
CADD	25.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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: PYGL
Protein: p.Asp422Val
Coding: c.1265A>T
MANE Select: NM_002863
Type: single nucleotide variant
Location: chr14:50915474 (GRCh38)
Gene constraint: LOEUF 1.048 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.87 · 19 PDB

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PYGL p.Asp422= Likely benign ★ same residue
PYGL p.Ala108Thr Uncertain significance ★★ ⚠ same condition
PYGL p.Ala704Thr Uncertain significance ★★ ⚠ same condition
PYGL p.Asn847Ile Uncertain significance ★★ ⚠ same condition
PYGL p.Asp110Val Uncertain significance ★★ ⚠ same condition
PYGL p.Asp528Asn Uncertain significance ★★ ⚠ same condition
PYGL p.Gly159Ser Uncertain significance ★★ ⚠ same condition
PYGL p.Gly449Ser 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/pygl-p-asp422val (accessed [today's date]).

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