Is PIGN p.Val528Ala (c.1583T>C) pathogenic?

PIGN p.Val528Ala (c.1583T>C) is classified Uncertain significance in PIGN (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-07). AlphaMissense: likely benign (0.2043); Very rare (popmax 0.00135%, afr); Associated with Inborn genetic diseases.

What condition is associated with PIGN p.Val528Ala (c.1583T>C)?

PIGN p.Val528Ala (c.1583T>C) is associated with Inborn genetic diseases (ClinVar).

How common is PIGN p.Val528Ala (c.1583T>C) in the general population?

PIGN p.Val528Ala (c.1583T>C) is very rare (popmax 0.00135%, afr) (gnomAD).

What do computational predictors say about PIGN p.Val528Ala (c.1583T>C)?

AlphaMissense predicts likely benign (score 0.2043) — an in-silico prediction, not a clinical call.

PIGN p.Val528Ala

c.1583T>C · VCV4136586

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2043 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00135%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2043	likely benign
REVEL	0.173	moderately benign-leaning
SaProt	LLR -8.31	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 11	GERP 2.1, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 109 kb · p 0.83 · regional, not allelic
Overall
CADD	22.0	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 0.00135% African / African-American · 1/73,826 alleles

Overall 6.36e-05% 1/1,572,028 alleles · very rare exomes 0/1,419,814 · genomes 1/152,214 · 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: PIGN
Protein: p.Val528Ala
Coding: c.1583T>C
MANE Select: NM_176787
Type: single nucleotide variant
Location: chr18:62107077 (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

Similar variants

PIGN c.1675-1G>T Pathogenic/Likely pathogenic ★★ same condition
PIGN p.Arg613Ter Pathogenic/Likely pathogenic ★★ same condition
PIGN p.Arg785His Likely pathogenic ★★ same condition
PIGN p.Arg95Trp Pathogenic/Likely pathogenic ★★ same condition
PIGN p.Leu311Trp Pathogenic/Likely pathogenic ★★ same condition
PIGN p.Ala100Thr Uncertain significance ★★ ⚠ same condition
PIGN p.Ala805Thr Uncertain significance ★★ ⚠ same condition
PIGN p.Ala829Thr Uncertain significance ★★ ⚠ 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-val528ala (accessed [today's date]).

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