Is LRBA p.Pro1269Ala (c.3805C>G) pathogenic?

LRBA p.Pro1269Ala (c.3805C>G) is classified Conflicting classifications of pathogenicity in LRBA (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-03-15). AlphaMissense: likely benign (0.0651); Ultra-rare (popmax 0.0847%, sas); Associated with Inborn genetic diseases.

What condition is associated with LRBA p.Pro1269Ala (c.3805C>G)?

LRBA p.Pro1269Ala (c.3805C>G) is associated with Inborn genetic diseases, combined immunodeficiency due to LRBA deficiency (ClinVar).

How common is LRBA p.Pro1269Ala (c.3805C>G) in the general population?

LRBA p.Pro1269Ala (c.3805C>G) is ultra-rare (popmax 0.0847%, sas) (gnomAD).

What do computational predictors say about LRBA p.Pro1269Ala (c.3805C>G)?

AlphaMissense predicts likely benign (score 0.0651) — an in-silico prediction, not a clinical call.

LRBA p.Pro1269Ala

c.3805C>G · rs555169864 · VCV1008889

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0651 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0847%, sas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0651	likely benign
REVEL	0.083	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 1.2	GERP 1.4, phastCons 0.72
Regional constraint	o/e 0.95	unconstrained · MANE · 749 kb · p 0.0015 · regional, not allelic
Overall
CADD	14.84	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0847% South Asian · 77/90,924 alleles

Filtering AF 0.0694% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0638%

Overall 0.00496% 80/1,613,316 alleles · ultra-rare exomes 73/1,460,984 · genomes 7/152,332 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0847%	1,181
Middle Eastern	0.0165%	6,060
Remaining individualsnot grpmax-eligible	0.0032%	31,242

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.Pro1269Ala
Coding: c.3805C>G
MANE Select: NM_001364905
dbSNP: rs555169864
Type: single nucleotide variant
Location: chr4:150851905 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: combined immunodeficiency due to LRBA deficiency

Similar variants

LRBA p.Pro1269= Likely benign ★ 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
LRBA c.5646-2A>T 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-pro1269ala (accessed [today's date]).

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