Is PIGN p.Ala496= (c.1488A>G) pathogenic?

PIGN p.Ala496= (c.1488A>G) is classified Benign in PIGN (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-03). Common (popmax 7.16%, eas) — too common for a highly-penetrant pathogenic allele; Associated with Inborn genetic diseases.

What condition is associated with PIGN p.Ala496= (c.1488A>G)?

PIGN p.Ala496= (c.1488A>G) is associated with Inborn genetic diseases, multiple congenital anomalies-hypotonia-seizures syndrome 1 (ClinVar).

PIGN p.Ala496=

Q: How common is PIGN p.Ala496= (c.1488A>G) in the general population?

PIGN p.Ala496= (c.1488A>G) is common (popmax 7.16%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1488A>G · rs2298784 · VCV472211

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Common

common (popmax 7.16%, eas) — too common for a highly-penetrant pathogenic allele

Conditions

Inborn genetic diseases

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 -1.3	GERP -2.3
Overall
CADD	8.122	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 7.16% East Asian · 3,205/44,778 alleles

Filtering AF 6.95% ClinGen BA1/BS1 input FAF95, joint · FAF99 6.87%

Overall 0.61% 9,838/1,613,146 alleles · common exomes 8,369/1,461,056 · genomes 1,469/152,090 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	7.16%	14
Finnishnot grpmax-eligible	6.4%	16
Remaining individualsnot grpmax-eligible	0.737%	136
Ashkenazi Jewishnot grpmax-eligible	0.409%	245
South Asian	0.295%	339
African / African-American	0.257%	388
Middle Eastern	0.132%	757
European (non-Finnish)	0.123%	813
Admixed American	0.0667%	1,499

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.Ala496=
Coding: c.1488A>G
MANE Select: NM_176787
dbSNP: rs2298784
Type: single nucleotide variant
Location: chr18:62109920 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: multiple congenital anomalies-hypotonia-seizures syndrome 1

Similar variants

PIGN p.Ala496Thr Uncertain significance ★ ⚠ same residue
PIGN p.Ala496fs Pathogenic ★ 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-ala496 (accessed [today's date]).

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