Is BTN2A2 p.Glu339Lys (c.1015G>A) pathogenic?

BTN2A2 p.Glu339Lys (c.1015G>A) is classified Uncertain significance in BTN2A2 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-04-16). AlphaMissense: likely pathogenic (0.634); Ultra-rare (popmax 0.0442%, nfe).

How common is BTN2A2 p.Glu339Lys (c.1015G>A) in the general population?

BTN2A2 p.Glu339Lys (c.1015G>A) is ultra-rare (popmax 0.0442%, nfe) (gnomAD).

What do computational predictors say about BTN2A2 p.Glu339Lys (c.1015G>A)?

AlphaMissense predicts likely pathogenic (score 0.634) — an in-silico prediction, not a clinical call.

BTN2A2 p.Glu339Lys

c.1015G>A · rs138172438 · VCV2351381

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.634 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0442%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.634	likely pathogenic · top 10% in BTN2A2
REVEL	0.108	moderately benign-leaning
SaProt	LLR -7.44	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.26 · evaluated, not missing
Constraint at this position
Conservation	phyloP 1.4	GERP -0.14, phastCons 0.88
Regional constraint	o/e 0.94	unconstrained · MANE · 9,142 bp · p 0.12 · regional, not allelic
Overall
CADD	17.95	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 0.0442% European (non-Finnish) · 521/1,180,028 alleles

Filtering AF 0.041% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0398%

Overall 0.0354% 572/1,614,186 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0442%	2,265
Remaining individualsnot grpmax-eligible	0.0416%	2,404
Admixed American	0.015%	6,669
Finnishnot grpmax-eligible	0.0125%	8,006
African / African-American	0.00933%	10,720
South Asian	0.0011%	91,086

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: BTN2A2
Protein: p.Glu339Lys
Coding: c.1015G>A
MANE Select: NM_006995
dbSNP: rs138172438
Type: single nucleotide variant
Location: chr6:26392410 (GRCh38)
Gene constraint: LOEUF 1.093 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.50 · 1 PDB
Residue 339: the b30.2/spry domain

Full BTN2A2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

BTN2A2 p.Glu339Asp Uncertain significance ★ ⚠ same residue
BTN2A2 p.Ala147Gly Uncertain significance ★ ⚠ same type
BTN2A2 p.Ala199Thr Uncertain significance ★ ⚠ same type
BTN2A2 p.Ala201Pro Uncertain significance ★ ⚠ same type
BTN2A2 p.Ala210Ser Uncertain significance ★ ⚠ same type
BTN2A2 p.Ala248Glu Uncertain significance ★ ⚠ same type
BTN2A2 p.Ala248Pro Uncertain significance ★ ⚠ same type
BTN2A2 p.Ala254Thr 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/btn2a2-p-glu339lys (accessed [today's date]).

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