Is RELA p.Arg274Trp (c.820C>T) pathogenic?

RELA p.Arg274Trp (c.820C>T) is classified Uncertain significance in RELA (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-20). AlphaMissense: likely pathogenic (0.9994); Very rare (popmax 0.00167%, amr).

How common is RELA p.Arg274Trp (c.820C>T) in the general population?

RELA p.Arg274Trp (c.820C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about RELA p.Arg274Trp (c.820C>T)?

AlphaMissense predicts likely pathogenic (score 0.9994) — an in-silico prediction, not a clinical call.

RELA p.Arg274Trp

c.820C>T · rs1252847592 · VCV1713667

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9994 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9994	likely pathogenic · top 9% in RELA
REVEL	0.699	pathogenic-leaning
SaProt	LLR -13.54	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 3.8	GERP -3.1, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 4,007 bp · p 0.25 · regional, not allelic
Overall
CADD	24.7	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

Grpmax group 0.00167% Admixed American · 1/59,768 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000186% 3/1,612,856 alleles · very rare exomes 3/1,460,556 · genomes 0/152,300 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	59,768
European (non-Finnish)	0.00017%	589,810

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: RELA
Protein: p.Arg274Trp
Coding: c.820C>T
MANE Select: NM_021975
dbSNP: rs1252847592
Type: single nucleotide variant
Location: chr11:65658344 (GRCh38)
Gene constraint: LOEUF 0.4 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 73.52 · 88 PDB
Residue 274: the rhd domain; a UniProt-annotated variant site (found in a patient diagnosed with autoimmune lymphoproliferative syndrome; uncertain significance); a β-strand

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

Similar variants

RELA p.Arg198Ter Pathogenic/Likely pathogenic ★★ same type
RELA p.Arg236Ter Pathogenic/Likely pathogenic ★★ same type
RELA p.Arg329Ter Pathogenic/Likely pathogenic ★★ same type
RELA p.Gln372Ter Pathogenic/Likely pathogenic ★★ same type
RELA p.Ala264Val Uncertain significance ★★ ⚠ same type
RELA p.Ala404Pro Uncertain significance ★★ ⚠ same type
RELA p.Ala404Thr Uncertain significance ★★ ⚠ same type
RELA p.Ala538Thr 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/rela-p-arg274trp (accessed [today's date]).

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