Is PIGN p.Ser561Arg (c.1683T>A) pathogenic?

PIGN p.Ser561Arg (c.1683T>A) is classified Uncertain significance in PIGN (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-01). AlphaMissense: likely pathogenic (0.9933); Very rare (popmax 0.00153%, nfe); Associated with multiple congenital anomalies-hypotonia-seizures syndrome 1.

What condition is associated with PIGN p.Ser561Arg (c.1683T>A)?

PIGN p.Ser561Arg (c.1683T>A) is associated with multiple congenital anomalies-hypotonia-seizures syndrome 1 (ClinVar).

How common is PIGN p.Ser561Arg (c.1683T>A) in the general population?

PIGN p.Ser561Arg (c.1683T>A) is very rare (popmax 0.00153%, nfe) (gnomAD).

What do computational predictors say about PIGN p.Ser561Arg (c.1683T>A)?

AlphaMissense predicts likely pathogenic (score 0.9933) — an in-silico prediction, not a clinical call.

PIGN p.Ser561Arg

c.1683T>A · rs2512959739 · VCV2105325

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9933 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00153%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

multiple congenital anomalies-hypotonia-seizures syndrome 1

Computational evidence

Protein change
AlphaMissense	0.9933	likely pathogenic · top 1% in PIGN
REVEL	0.512	indeterminate
SaProt	LLR -16.22	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.4	GERP 2.1, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 109 kb · p 0.83 · regional, not allelic
Overall
CADD	23.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00153% European (non-Finnish) · 18/1,176,484 alleles

Filtering AF 0.000956% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000789%

Overall 0.00118% 19/1,606,982 alleles · very rare exomes 19/1,454,672 · genomes 0/152,310 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00161%	62,282
European (non-Finnish)grpmax	0.00153%	65,360

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ser561Arg
Coding: c.1683T>A
MANE Select: NM_176787
dbSNP: rs2512959739
Type: single nucleotide variant
Location: chr18:62106873 (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-ser561arg (accessed [today's date]).

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