Is PIGN p.Ser688Arg (c.2062A>C) pathogenic?

PIGN p.Ser688Arg (c.2062A>C) is classified Conflicting classifications of pathogenicity in PIGN (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-09-30). AlphaMissense: likely pathogenic (0.9949); Very rare (popmax 8.56e-05%, nfe); Associated with multiple congenital anomalies-hypotonia-seizures syndrome 1.

What condition is associated with PIGN p.Ser688Arg (c.2062A>C)?

PIGN p.Ser688Arg (c.2062A>C) is associated with multiple congenital anomalies-hypotonia-seizures syndrome 1 (ClinVar).

How common is PIGN p.Ser688Arg (c.2062A>C) in the general population?

PIGN p.Ser688Arg (c.2062A>C) is very rare (popmax 8.56e-05%, nfe) (gnomAD).

What do computational predictors say about PIGN p.Ser688Arg (c.2062A>C)?

AlphaMissense predicts likely pathogenic (score 0.9949) — an in-silico prediction, not a clinical call.

PIGN p.Ser688Arg

c.2062A>C · rs1251827296 · VCV807656

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9949 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.56e-05%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

multiple congenital anomalies-hypotonia-seizures syndrome 1

Computational evidence

Protein change
AlphaMissense	0.9949	likely pathogenic · top 1% in PIGN
REVEL	0.636	indeterminate
SaProt	LLR -18.32	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.9	GERP 2.1, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 109 kb · p 0.83 · regional, not allelic
Overall
CADD	26.4	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 8.56e-05% European (non-Finnish) · 1/1,168,656 alleles

Overall 6.24e-05% 1/1,601,332 alleles · very rare exomes 0/1,449,124 · genomes 1/152,208 · 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.Ser688Arg
Coding: c.2062A>C
MANE Select: NM_176787
dbSNP: rs1251827296
Type: single nucleotide variant
Location: chr18:62101090 (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 p.Ser688Asn Uncertain significance ★ ⚠ 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
PIGN c.1675-1G>T Pathogenic/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-ser688arg (accessed [today's date]).

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