Is LRBA p.Ala1626Val (c.4877C>T) pathogenic?

LRBA p.Ala1626Val (c.4877C>T) is classified Uncertain significance in LRBA (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-01). AlphaMissense: likely benign (0.0654); Very rare (popmax 0.00669%, nfe); Associated with combined immunodeficiency due to LRBA deficiency.

What condition is associated with LRBA p.Ala1626Val (c.4877C>T)?

LRBA p.Ala1626Val (c.4877C>T) is associated with combined immunodeficiency due to LRBA deficiency (ClinVar).

How common is LRBA p.Ala1626Val (c.4877C>T) in the general population?

LRBA p.Ala1626Val (c.4877C>T) is very rare (popmax 0.00669%, nfe) (gnomAD).

What do computational predictors say about LRBA p.Ala1626Val (c.4877C>T)?

AlphaMissense predicts likely benign (score 0.0654) — an in-silico prediction, not a clinical call.

LRBA p.Ala1626Val

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.4877C>T · rs377211427 · VCV955157

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0654 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00669%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

combined immunodeficiency due to LRBA deficiency

Computational evidence

Protein change
AlphaMissense	0.0654	likely benign
REVEL	0.052	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 -0.006	GERP -3
Regional constraint	o/e 0.95	unconstrained · MANE · 749 kb · p 0.0015 · regional, not allelic
Overall
CADD	15.24	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.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00669% European (non-Finnish) · 79/1,180,006 alleles

Filtering AF 0.00546% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00506%

Overall 0.0057% 92/1,613,992 alleles · very rare exomes 87/1,461,836 · genomes 5/152,156 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0192%	5,207
European (non-Finnish)grpmax	0.00669%	14,937
Admixed American	0.00167%	59,996

Remaining individuals 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: LRBA
Protein: p.Ala1626Val
Coding: c.4877C>T
MANE Select: NM_001364905
dbSNP: rs377211427
Type: single nucleotide variant
Location: chr4:150828474 (GRCh38)
Gene constraint: LOEUF 0.515 · pLI <0.01 (gnomAD)
Residue 1626: the 'disordered' region

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 p.Ala1626Thr Uncertain significance ★ ⚠ same residue
LRBA p.Ala1626Leu Uncertain significance ★★ same residue
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

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-ala1626val (accessed [today's date]).

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