Is REL p.Phe220Ser (c.659T>C) pathogenic?

REL p.Phe220Ser (c.659T>C) is classified Uncertain significance in REL (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-23). AlphaMissense: likely pathogenic (0.9999); Absent from gnomAD v4.1; Associated with immunodeficiency 92.

What condition is associated with REL p.Phe220Ser (c.659T>C)?

REL p.Phe220Ser (c.659T>C) is associated with immunodeficiency 92 (ClinVar).

How common is REL p.Phe220Ser (c.659T>C) in the general population?

REL p.Phe220Ser (c.659T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about REL p.Phe220Ser (c.659T>C)?

AlphaMissense predicts likely pathogenic (score 0.9999) — an in-silico prediction, not a clinical call.

REL p.Phe220Ser

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.659T>C · VCV3256112

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9999 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

immunodeficiency 92

Computational evidence

Protein change
AlphaMissense	0.9999	likely pathogenic · top 4% in REL
REVEL	0.841	moderately pathogenic-leaning
SaProt	LLR -15.80	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 1.9, phastCons 1
Regional constraint	o/e 0.69	unconstrained · MANE · 29 kb · p 1.3e-08 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: REL
Protein: p.Phe220Ser
Coding: c.659T>C
MANE Select: NM_001291746
Type: single nucleotide variant
Location: chr2:60918412 (GRCh38)
Gene constraint: LOEUF 0.416 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 66.46
Residue 220: the rhd domain

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.992-7C>A Conflicting classifications of pathogenicity ★ same condition
REL c.395-1G>A Pathogenic same condition
REL c.535+1G>A Pathogenic same condition
REL c.923-171_923-170del Uncertain significance ★ same condition
REL p.Met571fs Uncertain significance ★ same condition
REL p.Asp224Asn Uncertain significance ★★ ⚠ same type

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-phe220ser (accessed [today's date]).

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