Is BTNL9 p.Asp467Glu (c.1401C>A) pathogenic?

BTNL9 p.Asp467Glu (c.1401C>A) is classified Uncertain significance in BTNL9 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-10). AlphaMissense: likely pathogenic (0.8159); Ultra-rare (popmax 0.0893%, afr).

How common is BTNL9 p.Asp467Glu (c.1401C>A) in the general population?

BTNL9 p.Asp467Glu (c.1401C>A) is ultra-rare (popmax 0.0893%, afr) (gnomAD).

What do computational predictors say about BTNL9 p.Asp467Glu (c.1401C>A)?

AlphaMissense predicts likely pathogenic (score 0.8159) — an in-silico prediction, not a clinical call.

BTNL9 p.Asp467Glu

c.1401C>A · VCV4216894

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8159 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0893%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8159	likely pathogenic · top 10% in BTNL9
REVEL	0.09	moderately benign-leaning
SaProt	LLR -7.13	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -5.7
Regional constraint	o/e 1.07	unconstrained · MANE · 14 kb · p 0.044 · regional, not allelic
Overall
CADD	14.43	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 0.0893% African / African-American · 67/75,054 alleles

Filtering AF 0.0721% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0658%

Overall 0.00428% 69/1,613,676 alleles · ultra-rare exomes 34/1,461,328 · genomes 35/152,348 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0893%	1,120
Remaining individualsnot grpmax-eligible	0.0032%	31,250

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.Asp467Glu
Coding: c.1401C>A
MANE Select: NM_152547
Type: single nucleotide variant
Location: chr5:181059655 (GRCh38)
Gene constraint: LOEUF 1.325 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.28
Residue 467: the b30.2/spry domain

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

Similar variants

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
BTNL9 p.Ala335Thr 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-asp467glu (accessed [today's date]).

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