Is LRBA p.Arg167Ser (c.499C>A) pathogenic?

LRBA p.Arg167Ser (c.499C>A) is classified Uncertain significance in LRBA (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-06-10). AlphaMissense: likely pathogenic (0.8543); Very rare (popmax 0.00223%, eas); Associated with Inborn genetic diseases.

What condition is associated with LRBA p.Arg167Ser (c.499C>A)?

LRBA p.Arg167Ser (c.499C>A) is associated with Inborn genetic diseases, combined immunodeficiency due to LRBA deficiency (ClinVar).

How common is LRBA p.Arg167Ser (c.499C>A) in the general population?

LRBA p.Arg167Ser (c.499C>A) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about LRBA p.Arg167Ser (c.499C>A)?

AlphaMissense predicts likely pathogenic (score 0.8543) — an in-silico prediction, not a clinical call.

LRBA p.Arg167Ser

c.499C>A · rs371936024 · VCV583400

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8543 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

1/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.8543	likely pathogenic
REVEL	0.205	benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense calls this damaging; REVEL does not; SaProt makes no call.
Splicing
SpliceAI	Δ0.20	donor loss, 50 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 7.2	GERP -0.88, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 749 kb · p 0.0015 · regional, not allelic
Overall
CADD	23.4	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 0.00223% East Asian · 1/44,850 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000248% 4/1,613,618 alleles · very rare exomes 3/1,461,620 · genomes 1/151,998 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,850
African / African-American	0.00134%	74,854
European (non-Finnish)	0.00017%	589,932

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.Arg167Ser
Coding: c.499C>A
MANE Select: NM_001364905
dbSNP: rs371936024
Type: single nucleotide variant
Location: chr4:150928566 (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.Arg167Cys Uncertain significance ★★ same residue
LRBA p.Arg167Gly Uncertain significance ★ same residue
LRBA p.Arg167His Uncertain significance ★ ⚠ same residue
MAB21L2 p.Val167Ala Uncertain significance ★ ⚠ same residue
LRBA p.Arg167= 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

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-arg167ser (accessed [today's date]).

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