Is BTNL9 p.Ala99Pro (c.295G>C) pathogenic?

BTNL9 p.Ala99Pro (c.295G>C) is classified Uncertain significance in BTNL9 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-04). AlphaMissense: likely benign (0.1215); Ultra-rare (popmax 0.015%, amr).

How common is BTNL9 p.Ala99Pro (c.295G>C) in the general population?

BTNL9 p.Ala99Pro (c.295G>C) is ultra-rare (popmax 0.015%, amr) (gnomAD).

What do computational predictors say about BTNL9 p.Ala99Pro (c.295G>C)?

AlphaMissense predicts likely benign (score 0.1215) — an in-silico prediction, not a clinical call.

BTNL9 p.Ala99Pro

c.295G>C · rs999171486 · VCV2367022

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1215 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.015%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1215	likely benign
REVEL	0.073	moderately benign-leaning
SaProt	LLR -7.61	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.2	GERP -1.4, phastCons 0.98
Regional constraint	o/e 1.07	unconstrained · MANE · 14 kb · p 0.044 · regional, not allelic
Overall
CADD	16.08	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 and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.015% Admixed American · 9/59,998 alleles

Filtering AF 0.00773% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00579%

Overall 0.000868% 14/1,613,522 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.015%	6,666
Remaining individualsnot grpmax-eligible	0.0064%	15,620
African / African-American	0.00133%	74,930

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: BTNL9
Protein: p.Ala99Pro
Coding: c.295G>C
MANE Select: NM_152547
dbSNP: rs999171486
Type: single nucleotide variant
Location: chr5:181048112 (GRCh38)
Gene constraint: LOEUF 1.325 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.28
Residue 99: a disulfide bond; the ig-like v-type domain

Full BTNL9 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

BTNL9 p.Ala99Val Uncertain significance ★ ⚠ same residue
BTNL9 p.Ala144Pro Uncertain significance ★ ⚠ same type
BTNL9 p.Ala200Val Uncertain significance ★ ⚠ same type
BTNL9 p.Ala252Val Uncertain significance ★ ⚠ same type
BTNL9 p.Ala261Thr Uncertain significance ★ ⚠ same type
BTNL9 p.Ala273Thr Uncertain significance ★ ⚠ same type
BTNL9 p.Ala291Glu Uncertain significance ★ ⚠ same type
BTNL9 p.Ala314Thr 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/btnl9-p-ala99pro (accessed [today's date]).

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