Is RELA p.Asp512fs (c.1533dup) pathogenic?

RELA p.Asp512fs (c.1533dup) is classified Uncertain significance in RELA (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-14). Very rare (popmax 0.00176%, amr).

How common is RELA p.Asp512fs (c.1533dup) in the general population?

RELA p.Asp512fs (c.1533dup) is very rare (popmax 0.00176%, amr) (gnomAD).

RELA p.Asp512fs

c.1533dup · rs753829254 · VCV1523950

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 0.00176%, amr)

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 (11 of 11) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.7	GERP 1.9, phastCons 1
Region caveats
Repeat context	seg dup	· reads may not map uniquely · confidence, not pathogenicity

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00176% Admixed American · 1/56,946 alleles

Overall 6.25e-05% 1/1,601,014 alleles · very rare exomes 1/1,448,694 · genomes 0/152,320 · joint denominator

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.Asp512fs
Coding: c.1533dup
MANE Select: NM_021975
dbSNP: rs753829254
Type: Duplication
Location: chr11:65654500 (GRCh38)
Gene constraint: LOEUF 0.4 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 73.52 · 88 PDB
Residue 512: a UniProt-annotated variant site (found in a patient diagnosed with autoimmune lymphoproliferative syndrome; uncertain significance); the 'disordered' region

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

Similar variants

RELA p.Asp512His Uncertain significance ★ ⚠ same residue
RELA p.Arg41fs Pathogenic ★ same type
RELA p.Asn137fs Pathogenic ★ same type
RELA p.Glu473fs Pathogenic ★ same type
RELA p.Ile118fs Pathogenic ★ same type
RELA p.Tyr306Ter Pathogenic ★ same type
RELA p.Tyr349fs Pathogenic ★ same type
RELA p.Ala396fs 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-asp512fs (accessed [today's date]).

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