Is RELA p.Asp449Ala (c.1346A>C) pathogenic?

RELA p.Asp449Ala (c.1346A>C) is classified Uncertain significance in RELA (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-28). AlphaMissense: ambiguous (0.3571); Very rare (popmax 0.000174%, nfe).

How common is RELA p.Asp449Ala (c.1346A>C) in the general population?

RELA p.Asp449Ala (c.1346A>C) is very rare (popmax 0.000174%, nfe) (gnomAD).

What do computational predictors say about RELA p.Asp449Ala (c.1346A>C)?

AlphaMissense predicts ambiguous (score 0.3571) — an in-silico prediction, not a clinical call.

RELA p.Asp449Ala

c.1346A>C · rs2496825253 · VCV1720630

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3571 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000174%, nfe)

Computational evidence

Protein change
AlphaMissense	0.3571	ambiguous
REVEL	0.302	indeterminate
SaProt	LLR -6.92	tolerated
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 6.1	GERP 1.9, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 4,007 bp · p 0.25 · regional, not allelic
Overall
CADD	25.3	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000174% European (non-Finnish) · 2/1,147,996 alleles

Filtering AF 2.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000129% 2/1,546,196 alleles · very rare exomes 2/1,393,922 · genomes 0/152,274 · 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.Asp449Ala
Coding: c.1346A>C
MANE Select: NM_021975
dbSNP: rs2496825253
Type: single nucleotide variant
Location: chr11:65654688 (GRCh38)
Gene constraint: LOEUF 0.4 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 73.52 · 88 PDB
Residue 449: a UniProt-annotated variant site (found in a patient diagnosed with autoimmune lymphoproliferative syndrome; uncertain significance); the 'transcriptional activation domain 1' region

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

Similar variants

RELA p.Asp449= Likely benign ★ same residue
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

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-asp449ala (accessed [today's date]).

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