Is PISD p.Arg366Pro (c.1097G>C) pathogenic?

PISD p.Arg366Pro (c.1097G>C) is classified Uncertain significance in PISD (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-01-06). AlphaMissense: likely pathogenic (0.585); Ultra-rare (popmax 0.0183%, amr); Associated with Inborn genetic diseases.

What condition is associated with PISD p.Arg366Pro (c.1097G>C)?

PISD p.Arg366Pro (c.1097G>C) is associated with Inborn genetic diseases (ClinVar).

How common is PISD p.Arg366Pro (c.1097G>C) in the general population?

PISD p.Arg366Pro (c.1097G>C) is ultra-rare (popmax 0.0183%, amr) (gnomAD).

What do computational predictors say about PISD p.Arg366Pro (c.1097G>C)?

AlphaMissense predicts likely pathogenic (score 0.585) — an in-silico prediction, not a clinical call.

PISD p.Arg366Pro

c.1097G>C · rs567105342 · VCV1427703

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.585 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0183%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.585	likely pathogenic
REVEL	0.167	moderately benign-leaning
SaProt	LLR -8.99	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.3	GERP 5.9, phastCons 1
Overall
CADD	25.6	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 0.0183% Admixed American · 11/60,030 alleles

Filtering AF 0.0102% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00785%

Overall 0.000867% 14/1,614,184 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0183%	5,457
Remaining individualsnot grpmax-eligible	0.0032%	31,255
European (non-Finnish)	8.47e-05%	1,179,998

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: PISD
Protein: p.Arg366Pro
Coding: c.1097G>C
MANE Select: NM_001326411
dbSNP: rs567105342
Type: single nucleotide variant
Location: chr22:31619745 (GRCh38)
Gene constraint: LOEUF 0.979 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.13

Full PISD gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PISD p.Arg366His Conflicting classifications of pathogenicity ★ ⚠ same residue
PISD p.Arg366= Likely benign ★ same residue
PISD p.Ala234Val Uncertain significance ★★ ⚠ same condition
PISD p.Ala386Val Uncertain significance ★★ ⚠ same condition
PISD p.Arg125Cys Uncertain significance ★★ ⚠ same condition
PISD p.Arg125His Uncertain significance ★★ ⚠ same condition
PISD p.Arg136His Uncertain significance ★★ ⚠ same condition
PISD p.Arg163Cys Uncertain significance ★★ ⚠ 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/pisd-p-arg366pro (accessed [today's date]).

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