Is ASPG p.Asp223= (c.669C>T) pathogenic?

ASPG p.Asp223= (c.669C>T) is classified Benign in ASPG (ClinVar, Multiple submitters, 2 submitters; last evaluated 2018-02-22). Common (popmax 5.34%, afr) — too common for a highly-penetrant pathogenic allele.

ASPG p.Asp223=

Q: How common is ASPG p.Asp223= (c.669C>T) in the general population?

ASPG p.Asp223= (c.669C>T) is common (popmax 5.34%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.669C>T · rs111758905 · VCV786627

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Common

common (popmax 5.34%, afr) — too common for a highly-penetrant pathogenic allele

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 -9.9	GERP -1.8
Overall
CADD	0.541	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 5.34% African / African-American · 3,899/73,082 alleles

Filtering AF 5.2% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.14%

Overall 0.287% 4,444/1,548,104 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	5.34%	19
Admixed American	0.396%	252
Remaining individualsnot grpmax-eligible	0.367%	272
Middle Eastern	0.229%	437
South Asian	0.0155%	6,458
European (non-Finnish)	0.00863%	11,583
Ashkenazi Jewishnot grpmax-eligible	0.00349%	28,632

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: ASPG
Protein: p.Asp223=
Coding: c.669C>T
MANE Select: NM_001080464
dbSNP: rs111758905
Type: single nucleotide variant
Location: chr14:104103591 (GRCh38)
Gene constraint: LOEUF 1.226 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.05 · 2 PDB
Residue 223: the asparaginase/glutaminase domain; the 'asparaginase' region

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

Similar variants

ASPG c.1620+1G>A Uncertain significance ★ same type
ASPG p.Ala315Gly Uncertain significance ★ ⚠ same type
ASPG p.Ala315Val Uncertain significance ★ ⚠ same type
ASPG p.Ala332Val Uncertain significance ★ ⚠ same type
ASPG p.Ala442Thr Uncertain significance ★ ⚠ same type
ASPG p.Ala4Thr Uncertain significance ★ ⚠ same type
ASPG p.Ala537Ser Uncertain significance ★ ⚠ same type
ASPG p.Ala53Pro Uncertain significance ★ ⚠ same type

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/aspg-p-asp223 (accessed [today's date]).

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