Is PIGN p.Val154Ile (c.460G>A) pathogenic?

PIGN p.Val154Ile (c.460G>A) is classified Uncertain significance in PIGN (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-08-21). AlphaMissense: likely benign (0.0726); Ultra-rare (popmax 0.0563%, eas); Associated with Inborn genetic diseases.

What condition is associated with PIGN p.Val154Ile (c.460G>A)?

PIGN p.Val154Ile (c.460G>A) is associated with Inborn genetic diseases, multiple congenital anomalies-hypotonia-seizures syndrome 1 (ClinVar).

How common is PIGN p.Val154Ile (c.460G>A) in the general population?

PIGN p.Val154Ile (c.460G>A) is ultra-rare (popmax 0.0563%, eas) (gnomAD).

What do computational predictors say about PIGN p.Val154Ile (c.460G>A)?

AlphaMissense predicts likely benign (score 0.0726) — an in-silico prediction, not a clinical call.

PIGN p.Val154Ile

c.460G>A · rs181730303 · VCV444435

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0726 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0563%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0726	likely benign
REVEL	0.089	moderately benign-leaning
SaProt	LLR -6.66	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 0.18	GERP -1.5, phastCons 0.66
Regional constraint	o/e 1.01	unconstrained · MANE · 109 kb · p 0.83 · regional, not allelic
Overall
CADD	16.48	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0563% East Asian · 25/44,426 alleles

Filtering AF 0.0391% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0333%

Overall 0.00246% 38/1,545,026 alleles · ultra-rare exomes 29/1,392,848 · genomes 9/152,178 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0563%	1,777
South Asian	0.00564%	17,722
Admixed American	0.00168%	59,478
Remaining individualsnot grpmax-eligible	0.00166%	60,074
European (non-Finnish)	0.000536%	186,728

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.Val154Ile
Coding: c.460G>A
MANE Select: NM_176787
dbSNP: rs181730303
Type: single nucleotide variant
Location: chr18:62154634 (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.Val154Leu Uncertain significance ★ same residue
PIGN p.Val154= Likely benign ★ 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-val154ile (accessed [today's date]).

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