Is PIGN p.Arg709Gln (c.2126G>A) pathogenic?

PIGN p.Arg709Gln (c.2126G>A) is classified Pathogenic in PIGN (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-07-31). AlphaMissense: ambiguous (0.3719); Ultra-rare (popmax 0.0164%, mid); Associated with multiple congenital anomalies-hypotonia-seizures syndrome 1.

What condition is associated with PIGN p.Arg709Gln (c.2126G>A)?

PIGN p.Arg709Gln (c.2126G>A) is associated with multiple congenital anomalies-hypotonia-seizures syndrome 1 (ClinVar).

How common is PIGN p.Arg709Gln (c.2126G>A) in the general population?

PIGN p.Arg709Gln (c.2126G>A) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about PIGN p.Arg709Gln (c.2126G>A)?

AlphaMissense predicts ambiguous (score 0.3719) — an in-silico prediction, not a clinical call.

PIGN p.Arg709Gln

c.2126G>A · rs397514475 · VCV30549

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.3719 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Conditions

multiple congenital anomalies-hypotonia-seizures syndrome 1

Computational evidence

Protein change
AlphaMissense	0.3719	ambiguous
REVEL	0.579	indeterminate
SaProt	LLR -12.16	damaging
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.30 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.6	GERP 1.8, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 109 kb · p 0.83 · regional, not allelic
Overall
CADD	28.2	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 0.0164% Middle Eastern · 1/6,082 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.00062% 10/1,613,092 alleles · ultra-rare exomes 8/1,461,024 · genomes 2/152,068 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,082
Remaining individualsnot grpmax-eligible	0.0048%	20,818
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,602
Admixed American	0.00167%	59,960
European (non-Finnish)	0.000339%	294,841

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.Arg709Gln
Coding: c.2126G>A
MANE Select: NM_176787
dbSNP: rs397514475
Type: single nucleotide variant
Location: chr18:62095902 (GRCh38)
Gene constraint: LOEUF 1.46 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 88.33
Residue 709: a UniProt-annotated variant site (in mcahs1)

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.Arg709Ter Pathogenic/Likely pathogenic ★★ same residue
PIGN p.Arg709Leu 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

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-arg709gln (accessed [today's date]).

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