Is PIGN p.Arg221Ter (c.661C>T) pathogenic?

PIGN p.Arg221Ter (c.661C>T) is classified Pathogenic in PIGN (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-22). Very rare (popmax 0.0049%, eas); Associated with multiple congenital anomalies-hypotonia-seizures syndrome 1.

What condition is associated with PIGN p.Arg221Ter (c.661C>T)?

PIGN p.Arg221Ter (c.661C>T) is associated with multiple congenital anomalies-hypotonia-seizures syndrome 1 (ClinVar).

How common is PIGN p.Arg221Ter (c.661C>T) in the general population?

PIGN p.Arg221Ter (c.661C>T) is very rare (popmax 0.0049%, eas) (gnomAD).

PIGN p.Arg221Ter

c.661C>T · rs1382897257 · VCV450902

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.0049%, eas)

Conditions

multiple congenital anomalies-hypotonia-seizures syndrome 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 8 of 31
Splicing
SpliceAI	Δ0.22	acceptor loss · deltas
Pangolin	Δ0.40	loss · gain 0.01 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 7.5	GERP 2, phastCons 1
Overall
CADD	47.0	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 0.0049% East Asian · 2/40,786 alleles

Filtering AF 0.000813% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000304%

Overall 0.000389% 6/1,542,724 alleles · very rare exomes 5/1,390,724 · genomes 1/152,000 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0049%	20,393
Admixed American	0.00197%	50,652
Remaining individualsnot grpmax-eligible	0.00167%	59,714
European (non-Finnish)	0.000175%	571,425

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: PIGN
Protein: p.Arg221Ter
Coding: c.661C>T
MANE Select: NM_176787
dbSNP: rs1382897257
Type: single nucleotide variant
Location: chr18:62148227 (GRCh38)
Gene constraint: LOEUF 1.46 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 88.33

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

Disease context

multiple congenital anomalies-hypotonia-seizures syndrome 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PIGN p.Arg221Gln Uncertain significance ★ ⚠ same residue
PIGN p.Arg221Leu Uncertain significance ★ same residue
PIGN c.1251+1G>A Pathogenic/Likely pathogenic ★★ same condition
PIGN c.1252-2A>G Pathogenic/Likely pathogenic ★★ same condition
PIGN c.1434+5G>A Pathogenic/Likely pathogenic ★★ same condition
PIGN c.1574+1G>A Likely pathogenic ★★ same condition
PIGN c.1674+1G>A Likely pathogenic ★★ same condition
PIGN c.1674+1G>C Pathogenic ★★ 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/pign-p-arg221ter (accessed [today's date]).

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