Is PIDD1 p.Arg342His (c.1025G>A) pathogenic?

PIDD1 p.Arg342His (c.1025G>A) is classified Uncertain significance in PIDD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-12). AlphaMissense: likely benign (0.1023); Ultra-rare (popmax 0.0107%, afr); Associated with Inborn genetic diseases.

What condition is associated with PIDD1 p.Arg342His (c.1025G>A)?

PIDD1 p.Arg342His (c.1025G>A) is associated with Inborn genetic diseases (ClinVar).

How common is PIDD1 p.Arg342His (c.1025G>A) in the general population?

PIDD1 p.Arg342His (c.1025G>A) is ultra-rare (popmax 0.0107%, afr) (gnomAD).

What do computational predictors say about PIDD1 p.Arg342His (c.1025G>A)?

AlphaMissense predicts likely benign (score 0.1023) — an in-silico prediction, not a clinical call.

PIDD1 p.Arg342His

c.1025G>A · rs375189720 · VCV2209912

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1023 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0107%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1023	likely benign
REVEL	0.103	moderately benign-leaning
SaProt	LLR -10.07	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.44 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.4	GERP 1.1, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 5,078 bp · p 0.0041 · regional, not allelic
Overall
CADD	22.6	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 0.0107% African / African-American · 8/74,988 alleles

Filtering AF 0.00528% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00447%

Overall 0.00521% 84/1,611,684 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0107%	9,373
European (non-Finnish)	0.00602%	16,616
East Asian	0.00446%	22,438
Admixed American	0.00334%	29,897
Remaining individualsnot grpmax-eligible	0.0016%	62,412

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.Arg342His
Coding: c.1025G>A
MANE Select: NM_145886
dbSNP: rs375189720
Type: single nucleotide variant
Location: chr11:802346 (GRCh38)
Gene constraint: LOEUF 1.237 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 50.02 · 2 PDB
Residue 342: the zu5 1 domain

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-arg342his (accessed [today's date]).

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