Is RELA p.Met366Thr (c.1097T>C) pathogenic?

RELA p.Met366Thr (c.1097T>C) is classified Uncertain significance in RELA (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-03). AlphaMissense: likely benign (0.112); Ultra-rare (popmax 0.0165%, mid).

How common is RELA p.Met366Thr (c.1097T>C) in the general population?

RELA p.Met366Thr (c.1097T>C) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about RELA p.Met366Thr (c.1097T>C)?

AlphaMissense predicts likely benign (score 0.112) — an in-silico prediction, not a clinical call.

RELA p.Met366Thr

c.1097T>C · VCV4767270

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.112 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.112	likely benign
REVEL	0.083	moderately benign-leaning
SaProt	LLR -5.40	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.2	GERP 0.97, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 4,007 bp · p 0.25 · regional, not allelic
Overall
CADD	19.37	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0165% Middle Eastern · 1/6,056 alleles

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

Overall 0.000187% 3/1,603,448 alleles · ultra-rare exomes 3/1,451,138 · genomes 0/152,310 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,056
European (non-Finnish)	0.00017%	587,789

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.Met366Thr
Coding: c.1097T>C
MANE Select: NM_021975
Type: single nucleotide variant
Location: chr11:65654937 (GRCh38)
Gene constraint: LOEUF 0.4 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 73.52 · 88 PDB
Residue 366: the 'transcriptional activation domain 3' region; a UniProt-annotated variant site (found in a patient diagnosed with autoimmune lymphoproliferative syndrome; uncertain significance)

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

Similar variants

RELA p.Met366Ile 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
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-met366thr (accessed [today's date]).

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