Is PIGN p.Ala496fs (c.1485del) pathogenic?

PIGN p.Ala496fs (c.1485del) is classified Pathogenic in PIGN (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-30). Very rare (popmax 0.005%, amr); Associated with multiple congenital anomalies-hypotonia-seizures syndrome 1.

What condition is associated with PIGN p.Ala496fs (c.1485del)?

PIGN p.Ala496fs (c.1485del) is associated with multiple congenital anomalies-hypotonia-seizures syndrome 1 (ClinVar).

How common is PIGN p.Ala496fs (c.1485del) in the general population?

PIGN p.Ala496fs (c.1485del) is very rare (popmax 0.005%, amr) (gnomAD).

PIGN p.Ala496fs

c.1485del · rs1568185349 · VCV935634

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

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 0.01	GERP -0.36

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.005% Admixed American · 3/59,978 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.000186% 3/1,613,208 alleles · very rare exomes 3/1,461,012 · genomes 0/152,196 · joint denominator

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.Ala496fs
Coding: c.1485del
MANE Select: NM_176787
dbSNP: rs1568185349
Type: Deletion
Location: chr18:62109923 (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.Ala496= Benign ★★ same residue
PIGN p.Ala496Thr Uncertain significance ★ ⚠ same residue
PIGN c.548_549+6del Pathogenic/Likely pathogenic ★★ same condition
PIGN c.806-4_808del Likely pathogenic ★★ same condition
PIGN p.Ile746fs Pathogenic/Likely pathogenic ★★ same condition
PIGN p.Leu420fs Pathogenic/Likely pathogenic ★★ same condition
PIGN p.Lys647fs Pathogenic ★★ same condition
PIGN c.1116+12del 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-ala496fs (accessed [today's date]).

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