Is REL p.Met571fs (c.1709_1710insCCAG) pathogenic?

REL p.Met571fs (c.17091710insCCAG) is classified Uncertain significance in REL (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-08). Very rare (popmax 0.00136%, nfe); Associated with immunodeficiency 92.

What condition is associated with REL p.Met571fs (c.1709_1710insCCAG)?

REL p.Met571fs (c.1709_1710insCCAG) is associated with immunodeficiency 92 (ClinVar).

How common is REL p.Met571fs (c.1709_1710insCCAG) in the general population?

REL p.Met571fs (c.1709_1710insCCAG) is very rare (popmax 0.00136%, nfe) (gnomAD).

REL p.Met571fs

Q: How is Combined immunodeficiency due to c-REL deficiency inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.1709_1710insCCAG · VCV3892275

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00136%, nfe)

Conditions

immunodeficiency 92

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a LoF-intolerant gene
NMD	escapes	premature termination codon in the last exon (10 of 10) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 4.9	GERP -0.35, phastCons 1
Overall
CADD	27.1	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00136% European (non-Finnish) · 16/1,179,608 alleles

Filtering AF 0.000803% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00065%

Overall 0.00105% 17/1,612,684 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00136%	73,726
African / African-American	0.00134%	74,868

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: REL
Protein: p.Met571fs
Coding: c.1709_1710insCCAG
MANE Select: NM_001291746
Type: Insertion
Location: chr2:60922477 (GRCh38)
Gene constraint: LOEUF 0.416 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 66.46

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

Disease context

immunodeficiency 92 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Combined immunodeficiency due to c-REL deficiency (Orphanet):

Inheritance: Autosomal recessive

Similar variants

REL p.Gln503His Uncertain significance ★★ ⚠ same condition
REL p.Met372Val Uncertain significance ★★ ⚠ same condition
REL c.923-171_923-170del Uncertain significance ★ same condition
REL c.992-7C>A Conflicting classifications of pathogenicity ★ same condition
REL p.Phe220Ser Uncertain significance ★ ⚠ same condition
REL c.395-1G>A Pathogenic same condition
REL c.535+1G>A Pathogenic 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/rel-p-met571fs (accessed [today's date]).

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