Is PIGN p.Val445Ile (c.1333G>A) pathogenic?

PIGN p.Val445Ile (c.1333G>A) is classified Conflicting classifications of pathogenicity in PIGN (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-01-13). AlphaMissense: likely benign (0.0577); Ultra-rare (popmax 0.0121%, sas); Associated with multiple congenital anomalies-hypotonia-seizures syndrome 1.

What condition is associated with PIGN p.Val445Ile (c.1333G>A)?

PIGN p.Val445Ile (c.1333G>A) is associated with multiple congenital anomalies-hypotonia-seizures syndrome 1 (ClinVar).

How common is PIGN p.Val445Ile (c.1333G>A) in the general population?

PIGN p.Val445Ile (c.1333G>A) is ultra-rare (popmax 0.0121%, sas) (gnomAD).

What do computational predictors say about PIGN p.Val445Ile (c.1333G>A)?

AlphaMissense predicts likely benign (score 0.0577) — an in-silico prediction, not a clinical call.

PIGN p.Val445Ile

c.1333G>A · rs187036839 · VCV586226

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0577 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0121%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

multiple congenital anomalies-hypotonia-seizures syndrome 1

Computational evidence

Protein change
AlphaMissense	0.0577	likely benign
REVEL	0.203	benign-leaning
SaProt	LLR -5.95	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.47	GERP -4
Regional constraint	o/e 1.01	unconstrained · MANE · 109 kb · p 0.83 · regional, not allelic
Overall
CADD	1.577	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0121% South Asian · 11/91,018 alleles

Filtering AF 0.00677% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00522%

Overall 0.00446% 72/1,612,726 alleles · ultra-rare exomes 64/1,460,484 · genomes 8/152,242 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0121%	8,274
Admixed American	0.01%	9,996
Remaining individualsnot grpmax-eligible	0.00641%	15,604
European (non-Finnish)	0.00407%	24,566
African / African-American	0.00267%	37,502
East Asian	0.00224%	44,736

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.Val445Ile
Coding: c.1333G>A
MANE Select: NM_176787
dbSNP: rs187036839
Type: single nucleotide variant
Location: chr18:62113235 (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 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
PIGN c.222-1G>A 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-val445ile (accessed [today's date]).

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