Is RELA p.Val199Ala (c.596T>C) pathogenic?

RELA p.Val199Ala (c.596T>C) is classified Conflicting classifications of pathogenicity in RELA (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-10-13). AlphaMissense: likely pathogenic (0.9888); Very rare (popmax 0.00134%, afr); Associated with autoinflammatory disease, familial, Behcet-like-3.

What condition is associated with RELA p.Val199Ala (c.596T>C)?

RELA p.Val199Ala (c.596T>C) is associated with autoinflammatory disease, familial, Behcet-like-3 (ClinVar).

How common is RELA p.Val199Ala (c.596T>C) in the general population?

RELA p.Val199Ala (c.596T>C) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about RELA p.Val199Ala (c.596T>C)?

AlphaMissense predicts likely pathogenic (score 0.9888) — an in-silico prediction, not a clinical call.

RELA p.Val199Ala

Q: How is Combined immunodeficiency due to RELA haploinsufficiency inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

c.596T>C · rs145138143 · VCV1342468

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9888 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

autoinflammatory disease, familial, Behcet-like-3

Computational evidence

Protein change
AlphaMissense	0.9888	likely pathogenic
REVEL	0.338	indeterminate
SaProt	LLR -9.66	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.7, phastCons 1
Regional constraint	o/e 0.58	unconstrained · MANE · 3,429 bp · p 2.3e-11 · regional, not allelic
Overall
CADD	25.2	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 0.00134% African / African-American · 1/74,782 alleles

Filtering AF 0.0005% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000366%

Overall 0.00279% 45/1,613,714 alleles · very rare exomes 39/1,461,872 · genomes 6/151,842 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.101%	987
Remaining individualsnot grpmax-eligible	0.0048%	20,829
African / African-Americangrpmax	0.00134%	74,782
European (non-Finnish)	0.000932%	107,268

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Val199Ala
Coding: c.596T>C
MANE Select: NM_021975
dbSNP: rs145138143
Type: single nucleotide variant
Location: chr11:65658786 (GRCh38)
Gene constraint: LOEUF 0.4 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 73.52 · 88 PDB
Residue 199: the rhd domain; a β-strand

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

Disease context

autoinflammatory disease, familial, Behcet-like-3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Combined immunodeficiency due to RELA haploinsufficiency (Orphanet):

Inheritance: Autosomal dominant
Onset: Childhood

Similar variants

RELA p.Val199= Likely benign ★ same residue
RELA p.Arg198Ter Pathogenic/Likely pathogenic ★★ same condition
RELA p.Arg329Ter Pathogenic/Likely pathogenic ★★ same condition
RELA p.Gln372Ter Pathogenic/Likely pathogenic ★★ same condition
RELA p.Arg325Gln Uncertain significance ★★ ⚠ same condition
RELA c.8-10C>T Benign/Likely benign ★★ same condition
RELA p.Asp291Asn Benign/Likely benign ★★ same condition
RELA p.Cys206Ter Likely pathogenic ★ same condition

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-val199ala (accessed [today's date]).

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