Is PIDD1 p.Arg761Pro (c.2282G>C) pathogenic?

PIDD1 p.Arg761Pro (c.2282G>C) is classified Uncertain significance in PIDD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-06). AlphaMissense: likely benign (0.1026); Very rare (popmax 0.00439%, sas); Associated with Inborn genetic diseases.

What condition is associated with PIDD1 p.Arg761Pro (c.2282G>C)?

PIDD1 p.Arg761Pro (c.2282G>C) is associated with Inborn genetic diseases (ClinVar).

How common is PIDD1 p.Arg761Pro (c.2282G>C) in the general population?

PIDD1 p.Arg761Pro (c.2282G>C) is very rare (popmax 0.00439%, sas) (gnomAD).

What do computational predictors say about PIDD1 p.Arg761Pro (c.2282G>C)?

AlphaMissense predicts likely benign (score 0.1026) — an in-silico prediction, not a clinical call.

PIDD1 p.Arg761Pro

c.2282G>C · VCV3306416

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1026 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00439%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1026	likely benign
REVEL	0.128	moderately benign-leaning
SaProt	LLR -5.76	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.16	GERP -2.1, phastCons 0.008
Regional constraint	o/e 1.08	unconstrained · MANE · 5,078 bp · p 0.0041 · regional, not allelic
Overall
CADD	11.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00439% South Asian · 4/91,080 alleles

Filtering AF 0.00143% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000891%

Overall 0.000434% 7/1,612,742 alleles · very rare exomes 7/1,460,416 · genomes 0/152,326 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00439%	22,770
European (non-Finnish)	0.000254%	393,287

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: PIDD1
Protein: p.Arg761Pro
Coding: c.2282G>C
MANE Select: NM_145886
Type: single nucleotide variant
Location: chr11:800007 (GRCh38)
Gene constraint: LOEUF 1.237 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 50.02 · 2 PDB
Residue 761: a UniProt-annotated variant site (in mrt75)

Full PIDD1 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

PIDD1 p.Arg551Cys Uncertain significance ★★ ⚠ same condition
PIDD1 p.Arg605Gln Uncertain significance ★★ ⚠ same condition
PIDD1 p.Arg742Ser Uncertain significance ★★ ⚠ same condition
PIDD1 p.Arg821Trp Uncertain significance ★★ ⚠ same condition
PIDD1 p.Arg842His Uncertain significance ★★ ⚠ same condition
PIDD1 p.Arg93His Uncertain significance ★★ ⚠ same condition
PIDD1 p.Gln197Glu Uncertain significance ★★ ⚠ same condition
PIDD1 p.Gly340Asp 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/pidd1-p-arg761pro (accessed [today's date]).

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