Is PIGN p.Lys478= (c.1434G>A) pathogenic?

PIGN p.Lys478= (c.1434G>A) is classified Uncertain significance in PIGN (ClinVar, Single submitter, 1 submitter; last evaluated 2018-05-17). Very rare (popmax 0.00336%, sas); Associated with multiple congenital anomalies-hypotonia-seizures syndrome 1.

What condition is associated with PIGN p.Lys478= (c.1434G>A)?

PIGN p.Lys478= (c.1434G>A) is associated with multiple congenital anomalies-hypotonia-seizures syndrome 1 (ClinVar).

How common is PIGN p.Lys478= (c.1434G>A) in the general population?

PIGN p.Lys478= (c.1434G>A) is very rare (popmax 0.00336%, sas) (gnomAD).

PIGN p.Lys478=

c.1434G>A · rs1336408586 · VCV571963

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00336%, sas)

Conditions

multiple congenital anomalies-hypotonia-seizures syndrome 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.86	donor loss · deltas
Pangolin	Δ0.67	loss · gain 0.06 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 7.7	GERP 2, phastCons 1
Overall
CADD	16.61	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00336% South Asian · 3/89,412 alleles

Filtering AF 0.000891% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000447%

Overall 0.000562% 9/1,600,956 alleles · very rare exomes 9/1,448,794 · genomes 0/152,162 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00336%	29,804
Remaining individualsnot grpmax-eligible	0.00161%	62,110
African / African-American	0.00134%	74,816
European (non-Finnish)	0.000341%	293,143

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.Lys478=
Coding: c.1434G>A
MANE Select: NM_176787
dbSNP: rs1336408586
Type: single nucleotide variant
Location: chr18:62113134 (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-lys478 (accessed [today's date]).

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