Is NT5E p.Ser221Ter (c.662C>A) pathogenic?

NT5E p.Ser221Ter (c.662C>A) is classified Pathogenic in NT5E (ClinVar, No assertion criteria, 1 submitter; last evaluated 2011-02-03). Ultra-rare (popmax 0.0227%, afr); Associated with hereditary arterial and articular multiple calcification syndrome.

What condition is associated with NT5E p.Ser221Ter (c.662C>A)?

NT5E p.Ser221Ter (c.662C>A) is associated with hereditary arterial and articular multiple calcification syndrome (ClinVar).

How common is NT5E p.Ser221Ter (c.662C>A) in the general population?

NT5E p.Ser221Ter (c.662C>A) is ultra-rare (popmax 0.0227%, afr) (gnomAD).

NT5E p.Ser221Ter

Q: How is Hereditary arterial and articular multiple calcification syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.662C>A · rs373328681 · VCV29687

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0227%, afr)

Conditions

hereditary arterial and articular multiple calcification syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 3 of 9
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.4, phastCons 1
Overall
CADD	37.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0227% African / African-American · 17/74,876 alleles

Filtering AF 0.0144% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0119%

Overall 0.00391% 63/1,612,910 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0227%	4,404
European (non-Finnish)	0.00373%	26,803
Remaining individualsnot grpmax-eligible	0.0032%	31,214

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: NT5E
Protein: p.Ser221Ter
Coding: c.662C>A
MANE Select: NM_002526
dbSNP: rs373328681
Type: single nucleotide variant
Location: chr6:85471336 (GRCh38)
Gene constraint: LOEUF 1.254 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.95 · 52 PDB
Residue 221: a β-strand

Full NT5E gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hereditary arterial and articular multiple calcification syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Hereditary arterial and articular multiple calcification syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Adult
Prevalence: <1 / 1 000 000 (Worldwide)

Similar variants

NT5E c.1210+12G>C Benign ★★ same condition
NT5E p.Thr376Ala Benign ★★ same condition
NT5E c.1104+2T>A Likely pathogenic ★ same condition
NT5E p.Ala322Val Uncertain significance ★ ⚠ same condition
NT5E p.Val278Ile Conflicting classifications of pathogenicity ★ ⚠ same condition
NT5E p.Cys358Tyr Pathogenic same condition
NT5E p.Val537fs Likely pathogenic ★★ same condition
NT5E p.Gly148= Likely benign ★★ 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/nt5e-p-ser221ter (accessed [today's date]).

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