Is RIPK1 p.Phe28= (c.84T>C) pathogenic?

RIPK1 p.Phe28= (c.84T>C) is classified Benign in RIPK1 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-02-04). Common (popmax 96.3%, nfe) — too common for a highly-penetrant pathogenic allele; Associated with autoinflammation with episodic fever and lymphadenopathy.

RIPK1 p.Phe28=

Q: What condition is associated with RIPK1 p.Phe28= (c.84T>C)?

RIPK1 p.Phe28= (c.84T>C) is associated with autoinflammation with episodic fever and lymphadenopathy, immunodeficiency 57 (ClinVar).

Q: How common is RIPK1 p.Phe28= (c.84T>C) in the general population?

RIPK1 p.Phe28= (c.84T>C) is common (popmax 96.3%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.84T>C · rs2272990 · VCV1166905

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Common

common (popmax 96.3%, nfe) — too common for a highly-penetrant pathogenic allele

Conditions

autoinflammation with episodic fever and lymphadenopathy

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -8.6	GERP -4
Overall
CADD	2.089	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 96.3% European (non-Finnish) · 1,135,540/1,179,046 alleles

Filtering AF 96.2% ClinGen BA1/BS1 input FAF95, joint · FAF99 96.1%

Overall 94.3% 1,519,458/1,611,990 alleles · common exomes 1,382,687/1,460,750 · genomes 136,771/151,240 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	98.4%	1
European (non-Finnish)grpmax	96.3%	1
Amishnot grpmax-eligible	96.1%	1
Middle Eastern	95.7%	1
South Asian	94.4%	1
Remaining individualsnot grpmax-eligible	93.2%	1
Finnishnot grpmax-eligible	90.1%	1
Admixed American	87.8%	1
African / African-American	81.6%	1
East Asian	74.1%	1

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: RIPK1
Protein: p.Phe28=
Coding: c.84T>C
MANE Select: NM_001354930
dbSNP: rs2272990
Type: single nucleotide variant
Location: chr6:3076907 (GRCh38)
Gene constraint: LOEUF 0.6 · pLI 0.21 (gnomAD)
Structure: AlphaFold pLDDT 70.38 · 39 PDB
Residue 28: the protein kinase domain; a binding site; a β-strand

Full RIPK1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

autoinflammation with episodic fever and lymphadenopathy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: immunodeficiency 57

Similar variants

RIPK1 p.Phe28Leu Uncertain significance ★★ ⚠ same residue
RIPK1 p.Asp324Asn Pathogenic ★★ ⚠ same condition
RIPK1 p.Asp324His Pathogenic ★★ ⚠ same condition
RIPK1 c.460-5C>A Uncertain significance ★★ same condition
RIPK1 p.Arg621Gln Uncertain significance ★★ ⚠ same condition
RIPK1 p.Ile123Thr Uncertain significance ★★ ⚠ same condition
RIPK1 c.688+2T>G Likely pathogenic ★ same condition
RIPK1 p.Ala155Gly 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/ripk1-p-phe28 (accessed [today's date]).

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