Is PIDD1 p.Ser226Phe (c.677C>T) pathogenic?

PIDD1 p.Ser226Phe (c.677C>T) is classified Uncertain significance in PIDD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-14). AlphaMissense: likely benign (0.2833); Very rare (popmax 0.00144%, nfe); Associated with Inborn genetic diseases.

What condition is associated with PIDD1 p.Ser226Phe (c.677C>T)?

PIDD1 p.Ser226Phe (c.677C>T) is associated with Inborn genetic diseases (ClinVar).

How common is PIDD1 p.Ser226Phe (c.677C>T) in the general population?

PIDD1 p.Ser226Phe (c.677C>T) is very rare (popmax 0.00144%, nfe) (gnomAD).

What do computational predictors say about PIDD1 p.Ser226Phe (c.677C>T)?

AlphaMissense predicts likely benign (score 0.2833) — an in-silico prediction, not a clinical call.

PIDD1 p.Ser226Phe

c.677C>T · rs373535114 · VCV2496126

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2833 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00144%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2833	likely benign
REVEL	0.259	benign-leaning
SaProt	LLR -7.94	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 4.9	GERP 1.7, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 5,078 bp · p 0.0041 · regional, not allelic
Overall
CADD	22.1	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 0.00144% European (non-Finnish) · 17/1,179,320 alleles

Filtering AF 0.000878% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000718%

Overall 0.00106% 17/1,610,330 alleles · very rare

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.Ser226Phe
Coding: c.677C>T
MANE Select: NM_145886
dbSNP: rs373535114
Type: single nucleotide variant
Location: chr11:803206 (GRCh38)
Gene constraint: LOEUF 1.237 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 50.02 · 2 PDB

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-ser226phe (accessed [today's date]).

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