Is BTNL2 p.Pro34Arg (c.101C>G) pathogenic?

BTNL2 p.Pro34Arg (c.101C>G) is classified Uncertain significance in BTNL2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-01). AlphaMissense: likely benign (0.1808); Ultra-rare (popmax 0.016%, afr).

How common is BTNL2 p.Pro34Arg (c.101C>G) in the general population?

BTNL2 p.Pro34Arg (c.101C>G) is ultra-rare (popmax 0.016%, afr) (gnomAD).

What do computational predictors say about BTNL2 p.Pro34Arg (c.101C>G)?

AlphaMissense predicts likely benign (score 0.1808) — an in-silico prediction, not a clinical call.

BTNL2 p.Pro34Arg

c.101C>G · rs373222791 · VCV3135549

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1808 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.016%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1808	likely benign
REVEL	0.37	indeterminate
SaProt	LLR -12.29	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.8, phastCons 1
Overall
CADD	22.9	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.016% African / African-American · 12/74,926 alleles

Filtering AF 0.00921% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00722%

Overall 0.000744% 12/1,612,912 alleles · ultra-rare

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: BTNL2
Protein: p.Pro34Arg
Coding: c.101C>G
MANE Select: NM_001304561
dbSNP: rs373222791
Type: single nucleotide variant
Location: chr6:32405265 (GRCh38)
Gene constraint: LOEUF 1.26 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.97
Residue 34: the ig-like v-type 1 domain

Full BTNL2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

BTNL2 p.Gly337Arg Uncertain significance ★★ same type
BTNL2 p.Ala12= Benign ★★ same type
BTNL2 c.709+6T>C Uncertain significance ★ same type
BTNL2 c.80-284C>G Uncertain significance ★ same type
BTNL2 p.Ala14Asp Uncertain significance ★ ⚠ same type
BTNL2 p.Ala14Ser Uncertain significance ★ ⚠ same type
BTNL2 p.Ala306Thr Uncertain significance ★ ⚠ same type
BTNL2 p.Ala430Thr Uncertain significance ★ ⚠ same type

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/btnl2-p-pro34arg (accessed [today's date]).

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