Is PIDD1 p.Val476Phe (c.1426G>T) pathogenic?

PIDD1 p.Val476Phe (c.1426G>T) is classified Uncertain significance in PIDD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-28). AlphaMissense: ambiguous (0.4491); Ultra-rare (popmax 0.0156%, sas); Associated with Inborn genetic diseases.

What condition is associated with PIDD1 p.Val476Phe (c.1426G>T)?

PIDD1 p.Val476Phe (c.1426G>T) is associated with Inborn genetic diseases (ClinVar).

How common is PIDD1 p.Val476Phe (c.1426G>T) in the general population?

PIDD1 p.Val476Phe (c.1426G>T) is ultra-rare (popmax 0.0156%, sas) (gnomAD).

What do computational predictors say about PIDD1 p.Val476Phe (c.1426G>T)?

AlphaMissense predicts ambiguous (score 0.4491) — an in-silico prediction, not a clinical call.

PIDD1 p.Val476Phe

c.1426G>T · rs369066278 · VCV3212610

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4491 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0156%, sas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4491	ambiguous
REVEL	0.237	benign-leaning
SaProt	LLR -10.26	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.63	GERP -2.8, phastCons 0.98
Regional constraint	o/e 1.08	unconstrained · MANE · 5,078 bp · p 0.0041 · regional, not allelic
Overall
CADD	22.2	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 0.0156% South Asian · 13/83,304 alleles

Filtering AF 0.00918% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00728%

Overall 0.00116% 18/1,551,464 alleles · ultra-rare exomes 17/1,399,236 · genomes 1/152,228 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0156%	6,408
Remaining individualsnot grpmax-eligible	0.00666%	15,006
European (non-Finnish)	8.72e-05%	1,146,817

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.Val476Phe
Coding: c.1426G>T
MANE Select: NM_145886
dbSNP: rs369066278
Type: single nucleotide variant
Location: chr11:801501 (GRCh38)
Gene constraint: LOEUF 1.237 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 50.02 · 2 PDB
Residue 476: the zu5 2 domain; 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-val476phe (accessed [today's date]).

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