Is PIDD1 p.Ser161Phe (c.482C>T) pathogenic?

PIDD1 p.Ser161Phe (c.482C>T) is classified Benign in PIDD1 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-03-01). AlphaMissense: likely benign (0.2012); Common (popmax 6.31%, afr) — too common for a highly-penetrant pathogenic allele; Associated with PIDD1-related disorder.

What condition is associated with PIDD1 p.Ser161Phe (c.482C>T)?

PIDD1 p.Ser161Phe (c.482C>T) is associated with PIDD1-related disorder (ClinVar).

What do computational predictors say about PIDD1 p.Ser161Phe (c.482C>T)?

AlphaMissense predicts likely benign (score 0.2012) — an in-silico prediction, not a clinical call.

PIDD1 p.Ser161Phe

Q: How common is PIDD1 p.Ser161Phe (c.482C>T) in the general population?

PIDD1 p.Ser161Phe (c.482C>T) is common (popmax 6.31%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.482C>T · rs61740131 · VCV3056059

Benign No assertion criteria

Classification

Benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2012 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 6.31%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

PIDD1-related disorder

Computational evidence

Protein change
AlphaMissense	0.2012	likely benign
REVEL	0.133	moderately benign-leaning
SaProt	LLR -10.62	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4.1	GERP 0.46, phastCons 0.83
Regional constraint	o/e 1.08	unconstrained · MANE · 5,078 bp · p 0.0041 · regional, not allelic
Overall
CADD	19.99	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 6.31% African / African-American · 4,733/75,030 alleles

Filtering AF 6.16% ClinGen BA1/BS1 input FAF95, joint · FAF99 6.1%

Overall 1.15% 18,493/1,613,946 alleles · common exomes 14,978/1,461,658 · genomes 3,515/152,288 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	6.31%	16
Amishnot grpmax-eligible	2.41%	41
Remaining individualsnot grpmax-eligible	1.22%	82
Ashkenazi Jewishnot grpmax-eligible	1%	100
European (non-Finnish)	0.99%	101
Admixed American	0.715%	140
Middle Eastern	0.643%	155
Finnishnot grpmax-eligible	0.42%	238
South Asian	0.284%	352
East Asian	0.00223%	44,882

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.Ser161Phe
Coding: c.482C>T
MANE Select: NM_145886
dbSNP: rs61740131
Type: single nucleotide variant
Location: chr11:803401 (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

PIDD1-related disorder

Similar variants

PIDD1 p.Glu734Lys Uncertain significance ★★ ⚠ same condition
PIDD1 c.2042-2A>G Conflicting classifications of pathogenicity ★ same condition
PIDD1 p.Gln391= Conflicting classifications of pathogenicity ★ same condition
PIDD1 c.2475-10C>T Likely benign same condition
PIDD1 c.710-4G>A Likely benign same condition
PIDD1 p.Ala670= Likely benign same condition
PIDD1 p.Arg549Leu Likely benign same condition
PIDD1 p.Arg652Trp Benign 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-ser161phe (accessed [today's date]).

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