Is PIGN p.Arg565Cys (c.1693C>T) pathogenic?

PIGN p.Arg565Cys (c.1693C>T) is classified Uncertain significance in PIGN (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-01-29). AlphaMissense: likely pathogenic (0.8155); Very rare (popmax 0.00936%, afr); Associated with multiple congenital anomalies-hypotonia-seizures syndrome 1.

What condition is associated with PIGN p.Arg565Cys (c.1693C>T)?

PIGN p.Arg565Cys (c.1693C>T) is associated with multiple congenital anomalies-hypotonia-seizures syndrome 1 (ClinVar).

How common is PIGN p.Arg565Cys (c.1693C>T) in the general population?

PIGN p.Arg565Cys (c.1693C>T) is very rare (popmax 0.00936%, afr) (gnomAD).

What do computational predictors say about PIGN p.Arg565Cys (c.1693C>T)?

AlphaMissense predicts likely pathogenic (score 0.8155) — an in-silico prediction, not a clinical call.

PIGN p.Arg565Cys

c.1693C>T · rs374005156 · VCV646762

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.8155 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00936%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

multiple congenital anomalies-hypotonia-seizures syndrome 1

Computational evidence

Protein change
AlphaMissense	0.8155	likely pathogenic
REVEL	0.795	moderately pathogenic-leaning
SaProt	LLR -13.00	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.38 · evaluated, not missing
Constraint at this position
Conservation	phyloP 9.9	GERP 2.1, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 109 kb · p 0.83 · regional, not allelic
Overall
CADD	33.0	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 0.00936% African / African-American · 7/74,750 alleles

Filtering AF 0.00743% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00694%

Overall 0.0074% 119/1,607,786 alleles · very rare exomes 111/1,455,760 · genomes 8/152,026 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00936%	10,679
East Asian	0.00897%	11,148
European (non-Finnish)	0.00884%	11,318
Remaining individualsnot grpmax-eligible	0.00321%	31,141
South Asian	0.00223%	44,821

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.Arg565Cys
Coding: c.1693C>T
MANE Select: NM_176787
dbSNP: rs374005156
Type: single nucleotide variant
Location: chr18:62106863 (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.Arg565His Uncertain significance ★★ ⚠ same residue
PIGN p.Arg565Leu Conflicting classifications of pathogenicity ★ ⚠ 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-arg565cys (accessed [today's date]).

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