Is PYGL p.Asp218= (c.654C>T) pathogenic?

PYGL p.Asp218= (c.654C>T) is classified Likely benign in PYGL (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-14). Ultra-rare (popmax 0.0214%, afr); Associated with Inborn genetic diseases.

What condition is associated with PYGL p.Asp218= (c.654C>T)?

PYGL p.Asp218= (c.654C>T) is associated with Inborn genetic diseases (ClinVar).

How common is PYGL p.Asp218= (c.654C>T) in the general population?

PYGL p.Asp218= (c.654C>T) is ultra-rare (popmax 0.0214%, afr) (gnomAD).

PYGL p.Asp218=

c.654C>T · VCV3941387

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0214%, afr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.6	GERP -3.9, phastCons 1
Overall
CADD	8.628	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0214% African / African-American · 16/74,894 alleles

Filtering AF 0.0133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0109%

Overall 0.00149% 24/1,613,648 alleles · ultra-rare exomes 15/1,461,470 · genomes 9/152,178 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0214%	4,681
Middle Eastern	0.0164%	6,082
Remaining individualsnot grpmax-eligible	0.0048%	20,825
Admixed American	0.00333%	30,000
South Asian	0.0022%	45,539

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: PYGL
Protein: p.Asp218=
Coding: c.654C>T
MANE Select: NM_002863
Type: single nucleotide variant
Location: chr14:50923975 (GRCh38)
Gene constraint: LOEUF 1.048 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.87 · 19 PDB
Residue 218: a β-strand

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.Asp218Asn Uncertain significance ★ ⚠ 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-asp218 (accessed [today's date]).

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