Is PIGN p.Thr176= (c.528G>A) pathogenic?

PIGN p.Thr176= (c.528G>A) is classified Benign/Likely benign in PIGN (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-03-01). Rare (popmax 0.975%, afr); Associated with Inborn genetic diseases.

What condition is associated with PIGN p.Thr176= (c.528G>A)?

PIGN p.Thr176= (c.528G>A) is associated with Inborn genetic diseases, multiple congenital anomalies-hypotonia-seizures syndrome 1 (ClinVar).

How common is PIGN p.Thr176= (c.528G>A) in the general population?

PIGN p.Thr176= (c.528G>A) is rare (popmax 0.975%, afr) (gnomAD).

PIGN p.Thr176=

c.528G>A · rs144304758 · VCV472233

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

rare (popmax 0.975%, afr)

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 -4.6	GERP -4
Overall
CADD	5.703	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.975% African / African-American · 718/73,606 alleles

Filtering AF 0.916% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.893%

Overall 0.0544% 843/1,550,590 alleles · rare exomes 428/1,398,404 · genomes 415/152,186 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.975%	103
Middle Eastern	0.134%	745
Remaining individualsnot grpmax-eligible	0.0597%	1,676
Admixed American	0.0284%	3,517
European (non-Finnish)	0.00525%	19,041
South Asian	0.00448%	22,327
East Asian	0.00225%	44,468

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.Thr176=
Coding: c.528G>A
MANE Select: NM_176787
dbSNP: rs144304758
Type: single nucleotide variant
Location: chr18:62154566 (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.Thr176Met 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
PIGN c.1675-1G>T Pathogenic/Likely 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-thr176 (accessed [today's date]).

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