Is REL p.Met372Val (c.1114A>G) pathogenic?

REL p.Met372Val (c.1114A>G) is classified Uncertain significance in REL (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-05-14). AlphaMissense: likely benign (0.058); Ultra-rare (popmax 0.0134%, eas); Associated with immunodeficiency 92.

What condition is associated with REL p.Met372Val (c.1114A>G)?

REL p.Met372Val (c.1114A>G) is associated with immunodeficiency 92 (ClinVar).

How common is REL p.Met372Val (c.1114A>G) in the general population?

REL p.Met372Val (c.1114A>G) is ultra-rare (popmax 0.0134%, eas) (gnomAD).

What do computational predictors say about REL p.Met372Val (c.1114A>G)?

AlphaMissense predicts likely benign (score 0.058) — an in-silico prediction, not a clinical call.

REL p.Met372Val

Q: How is Combined immunodeficiency due to c-REL deficiency inherited?

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

c.1114A>G · rs150652295 · VCV2186655

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.058 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0134%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

immunodeficiency 92

Computational evidence

Protein change
AlphaMissense	0.058	likely benign
REVEL	0.03	moderately benign-leaning
SaProt	LLR -5.76	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 -0.68	GERP -2.8
Regional constraint	o/e 1.00	unconstrained · MANE · 1,945 bp · p 0.96 · regional, not allelic
Overall
CADD	0.09	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM M404V vs ClinVar M372V) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0134% East Asian · 6/44,886 alleles

Filtering AF 0.00579% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00394%

Overall 0.00235% 38/1,613,924 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0134%	7,481
Remaining individualsnot grpmax-eligible	0.0064%	15,621
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,604
Admixed American	0.00333%	29,992
South Asian	0.0022%	45,544
European (non-Finnish)	0.00178%	56,191
Finnishnot grpmax-eligible	0.00156%	64,006
African / African-American	0.00134%	74,872

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: REL
Protein: p.Met372Val
Coding: c.1114A>G
MANE Select: NM_001291746
dbSNP: rs150652295
Type: single nucleotide variant
Location: chr2:60921885 (GRCh38)
Gene constraint: LOEUF 0.416 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 66.46

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

Disease context

immunodeficiency 92 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Combined immunodeficiency due to c-REL deficiency (Orphanet):

Inheritance: Autosomal recessive

Similar variants

REL p.Met372Lys Uncertain significance ★★ ⚠ same residue
REL p.Gln503His Uncertain significance ★★ ⚠ same condition
REL c.992-7C>A Conflicting classifications of pathogenicity ★ same condition
REL p.Phe220Ser Uncertain significance ★ ⚠ same condition
REL c.395-1G>A Pathogenic same condition
REL c.535+1G>A Pathogenic same condition
REL c.923-171_923-170del Uncertain significance ★ same condition
REL p.Met571fs Uncertain significance ★ 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/rel-p-met372val (accessed [today's date]).

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