Is RELA p.Ser536Cys (c.1607C>G) pathogenic?

RELA p.Ser536Cys (c.1607C>G) is classified Uncertain significance in RELA (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-01). AlphaMissense: ambiguous (0.4683); Very rare (popmax 8.48e-05%, nfe).

How common is RELA p.Ser536Cys (c.1607C>G) in the general population?

RELA p.Ser536Cys (c.1607C>G) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about RELA p.Ser536Cys (c.1607C>G)?

AlphaMissense predicts ambiguous (score 0.4683) — an in-silico prediction, not a clinical call.

RELA p.Ser536Cys

c.1607C>G · rs2496822643 · VCV2555080

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4683 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.4683	ambiguous
REVEL	0.16	moderately benign-leaning
SaProt	LLR -9.01	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 4,007 bp · p 0.25 · regional, not allelic
Overall
CADD	26.4	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 8.48e-05% European (non-Finnish) · 1/1,178,862 alleles

Overall 6.21e-05% 1/1,611,322 alleles · very rare exomes 1/1,459,038 · genomes 0/152,284 · 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.Ser536Cys
Coding: c.1607C>G
MANE Select: NM_021975
dbSNP: rs2496822643
Type: single nucleotide variant
Location: chr11:65654427 (GRCh38)
Gene constraint: LOEUF 0.4 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 73.52 · 88 PDB
Residue 536: a modified residue (phosphoserine; by ikkb); a UniProt-annotated variant site (found in a patient diagnosed with autoimmune lymphoproliferative syndrome; uncertain significance); the 'transcriptional activation domain 2' region; a turn

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

Similar variants

RELA p.Ser536= Likely benign ★★ same residue
RELA p.Ser536del Uncertain significance ★ 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

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-ser536cys (accessed [today's date]).

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