Is PIGN p.Leu499fs (c.1494dup) pathogenic?

PIGN p.Leu499fs (c.1494dup) is classified Pathogenic/Likely pathogenic in PIGN (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-10-15). Very rare (popmax 0.00223%, eas); Associated with multiple congenital anomalies-hypotonia-seizures syndrome 1.

What condition is associated with PIGN p.Leu499fs (c.1494dup)?

PIGN p.Leu499fs (c.1494dup) is associated with multiple congenital anomalies-hypotonia-seizures syndrome 1 (ClinVar).

How common is PIGN p.Leu499fs (c.1494dup) in the general population?

PIGN p.Leu499fs (c.1494dup) is very rare (popmax 0.00223%, eas) (gnomAD).

PIGN p.Leu499fs

c.1494dup · rs750418747 · VCV658963

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Conditions

multiple congenital anomalies-hypotonia-seizures syndrome 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 17 of 31
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 6.7	GERP 2.1, phastCons 1

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,786 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.00062% 10/1,613,250 alleles · very rare exomes 10/1,461,030 · genomes 0/152,220 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0032%	31,225
East Asiangrpmax	0.00223%	44,786
South Asian	0.0011%	91,052
European (non-Finnish)	0.000509%	196,575

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Leu499fs
Coding: c.1494dup
MANE Select: NM_176787
dbSNP: rs750418747
Type: Duplication
Location: chr18:62109913 (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.Ala273fs Pathogenic/Likely pathogenic ★★ same condition
PIGN p.Gly800fs Pathogenic ★★ same condition
PIGN p.Met328fs Pathogenic/Likely pathogenic ★★ same condition
PIGN c.1116+12dup Benign/Likely benign ★★ same condition
PIGN c.2577-13dup Benign/Likely benign ★★ same condition
PIGN c.2620-17_2620-15dup Likely benign ★★ same condition
PIGN c.2620-17_2620-16dup Benign/Likely benign ★★ same condition
PIGN c.2620-17dup Benign/Likely benign ★★ 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-leu499fs (accessed [today's date]).

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