Is RELA p.Pro381Leu (c.1142C>T) pathogenic?

RELA p.Pro381Leu (c.1142C>T) is classified Uncertain significance in RELA (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-06). AlphaMissense: likely benign (0.0857); Ultra-rare (popmax 0.059%, eas).

How common is RELA p.Pro381Leu (c.1142C>T) in the general population?

RELA p.Pro381Leu (c.1142C>T) is ultra-rare (popmax 0.059%, eas) (gnomAD).

What do computational predictors say about RELA p.Pro381Leu (c.1142C>T)?

AlphaMissense predicts likely benign (score 0.0857) — an in-silico prediction, not a clinical call.

RELA p.Pro381Leu

c.1142C>T · VCV3621733

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0857 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.059%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0857	likely benign
REVEL	0.031	moderately benign-leaning
SaProt	LLR -9.01	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 3.9	GERP 1.7, phastCons 0.86
Regional constraint	o/e 0.94	unconstrained · MANE · 4,007 bp · p 0.25 · regional, not allelic
Overall
CADD	17.56	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 0.059% East Asian · 26/44,052 alleles

Filtering AF 0.0413% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0354%

Overall 0.00196% 31/1,585,000 alleles · ultra-rare exomes 28/1,432,832 · genomes 3/152,168 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.059%	1,694
South Asian	0.00229%	43,695
European (non-Finnish)	0.000257%	388,426

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.Pro381Leu
Coding: c.1142C>T
MANE Select: NM_021975
Type: single nucleotide variant
Location: chr11:65654892 (GRCh38)
Gene constraint: LOEUF 0.4 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 73.52 · 88 PDB
Residue 381: 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.Pro381= 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-pro381leu (accessed [today's date]).

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