Is LRBA p.Pro2072Ser (c.6214C>T) pathogenic?

LRBA p.Pro2072Ser (c.6214C>T) is classified Uncertain significance in LRBA (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-02-08). AlphaMissense: likely benign (0.0639); Very rare (popmax 0.00883%, nfe); Associated with combined immunodeficiency due to LRBA deficiency.

What condition is associated with LRBA p.Pro2072Ser (c.6214C>T)?

LRBA p.Pro2072Ser (c.6214C>T) is associated with combined immunodeficiency due to LRBA deficiency (ClinVar).

How common is LRBA p.Pro2072Ser (c.6214C>T) in the general population?

LRBA p.Pro2072Ser (c.6214C>T) is very rare (popmax 0.00883%, nfe) (gnomAD).

What do computational predictors say about LRBA p.Pro2072Ser (c.6214C>T)?

AlphaMissense predicts likely benign (score 0.0639) — an in-silico prediction, not a clinical call.

LRBA p.Pro2072Ser

Q: How is Syndromic autoimmune enteropathy due to LRBA deficiency inherited?

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

c.6214C>T · rs140681994 · VCV571369

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0639 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00883%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

combined immunodeficiency due to LRBA deficiency

Computational evidence

Protein change
AlphaMissense	0.0639	likely benign
REVEL	0.151	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.6	GERP 2.9, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 749 kb · p 0.0015 · regional, not allelic
Overall
CADD	19.73	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 is an independent agreement signal.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P2083S vs ClinVar P2072S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00883% European (non-Finnish) · 104/1,177,806 alleles

Filtering AF 0.00742% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00694%

Overall 0.00696% 112/1,608,694 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00883%	11,325
Remaining individualsnot grpmax-eligible	0.00482%	20,766
African / African-American	0.00402%	24,894
Admixed American	0.00169%	59,272
South Asian	0.00112%	89,432

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: LRBA
Protein: p.Pro2072Ser
Coding: c.6214C>T
MANE Select: NM_001364905
dbSNP: rs140681994
Type: single nucleotide variant
Location: chr4:150588164 (GRCh38)
Gene constraint: LOEUF 0.515 · pLI <0.01 (gnomAD)

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

Disease context

combined immunodeficiency due to LRBA deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Syndromic autoimmune enteropathy due to LRBA deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy

Similar variants

LRBA c.216+1G>C Pathogenic/Likely pathogenic ★★ same condition
LRBA c.2259-2A>G Likely pathogenic ★★ same condition
LRBA c.2767-2A>G Likely pathogenic ★★ same condition
LRBA c.4159-1G>T Likely pathogenic ★★ same condition
LRBA c.5518+2T>C Likely pathogenic ★★ same condition
LRBA c.5519-1G>A Likely pathogenic ★★ same condition
LRBA c.5646-2A>T Pathogenic ★★ same condition
LRBA p.Arg1445Ter 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/lrba-p-pro2072ser (accessed [today's date]).

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