Is PIGN p.Ser893Arg (c.2679C>G) pathogenic?

PIGN p.Ser893Arg (c.2679C>G) is classified Conflicting classifications of pathogenicity in PIGN (ClinVar, Conflicting submitters, 10 submitters; last evaluated 2025-08-23). AlphaMissense: likely pathogenic (0.9969); Ultra-rare (popmax 0.0386%, sas); Associated with PIGN-related disorder.

What condition is associated with PIGN p.Ser893Arg (c.2679C>G)?

PIGN p.Ser893Arg (c.2679C>G) is associated with PIGN-related disorder, multiple congenital anomalies-hypotonia-seizures syndrome 1 (ClinVar).

How common is PIGN p.Ser893Arg (c.2679C>G) in the general population?

PIGN p.Ser893Arg (c.2679C>G) is ultra-rare (popmax 0.0386%, sas) (gnomAD).

What do computational predictors say about PIGN p.Ser893Arg (c.2679C>G)?

AlphaMissense predicts likely pathogenic (score 0.9969) — an in-silico prediction, not a clinical call.

PIGN p.Ser893Arg

c.2679C>G · rs199573774 · VCV449082

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 10 submitters

AlphaMissense

likely pathogenic

0.9969 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0386%, sas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

PIGN-related disorder

Computational evidence

Protein change
AlphaMissense	0.9969	likely pathogenic · top 1% in PIGN
REVEL	0.433	indeterminate
SaProt	LLR -14.69	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 2.9	GERP 0.33, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 109 kb · p 0.83 · regional, not allelic
Overall
CADD	23.4	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 0.0386% South Asian · 35/90,616 alleles

Filtering AF 0.0285% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.025%

Overall 0.00955% 154/1,612,328 alleles · ultra-rare exomes 131/1,460,002 · genomes 23/152,326 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0386%	2,589
Admixed American	0.0151%	6,644
Remaining individualsnot grpmax-eligible	0.00961%	10,407
European (non-Finnish)	0.0084%	11,910
Finnishnot grpmax-eligible	0.00625%	15,990
African / African-American	0.00133%	75,040

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.Ser893Arg
Coding: c.2679C>G
MANE Select: NM_176787
dbSNP: rs199573774
Type: single nucleotide variant
Location: chr18:62045973 (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

PIGN-related disorder

Also linked: multiple congenital anomalies-hypotonia-seizures syndrome 1

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-ser893arg (accessed [today's date]).

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