Is PIGG p.Pro45= (c.135A>C) pathogenic?

PIGG p.Pro45= (c.135A>C) is classified Likely benign in PIGG (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-17). Very rare (popmax 6.25e-05%); Associated with intellectual disability, autosomal recessive 53.

What condition is associated with PIGG p.Pro45= (c.135A>C)?

PIGG p.Pro45= (c.135A>C) is associated with intellectual disability, autosomal recessive 53 (ClinVar).

How common is PIGG p.Pro45= (c.135A>C) in the general population?

PIGG p.Pro45= (c.135A>C) is very rare (popmax 6.25e-05%) (gnomAD).

PIGG p.Pro45=

Q: How is Early-onset epilepsy-intellectual disability-brain anomalies syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.135A>C · rs1553874215 · VCV1592753

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 6.25e-05%)

Conditions

intellectual disability, autosomal recessive 53

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -3.8	GERP -3.1
Overall
CADD	3.433	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 6.25e-05%

Overall 6.25e-05% 1/1,600,126 alleles · very rare exomes 1/1,447,956 · genomes 0/152,170 · 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: PIGG
Protein: p.Pro45=
Coding: c.135A>C
MANE Select: NM_001127178
dbSNP: rs1553874215
Type: single nucleotide variant
Location: chr4:499470 (GRCh38)
Gene constraint: LOEUF 1.11 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.48

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

Disease context

intellectual disability, autosomal recessive 53 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Early-onset epilepsy-intellectual disability-brain anomalies syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Neonatal

Similar variants

PIGG c.570+1G>A Pathogenic/Likely pathogenic ★★ same condition
PIGG p.Arg304Ter Pathogenic ★★ same condition
PIGG p.Arg633Ter Pathogenic/Likely pathogenic ★★ same condition
PIGG p.Gln310Ter Pathogenic ★★ same condition
PIGG p.Gln411Ter Pathogenic/Likely pathogenic ★★ same condition
PIGG p.Gln851Pro Pathogenic/Likely pathogenic ★★ same condition
PIGG p.Gln857Ter Pathogenic/Likely pathogenic ★★ same condition
PIGG p.Glu256Ter 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/pigg-p-pro45 (accessed [today's date]).

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